Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general there is a decrease in the total white cell count (particularly the lymphocytes), a decrease in the platelet count, an increase in the blood serum liver enzymes, and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged.

The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection (such as for NS1) or specific antibodies (serology). Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost. Detection of NS1 during the febrile phase of a primary infection may be greater than 90% sensitive however is only 60–80% in subsequent infections. All tests may be negative in the early stages of the disease. PCR and viral antigen detection are more accurate in the first seven days. In 2012 a PCR test was introduced that can run on equipment used to diagnose influenza; this is likely to improve access to PCR-based diagnosis.

These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of serology. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in reinfection. IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection, IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. In testing for IgG and IgM antibodies there may be cross-reactivity with other flaviviruses which may result in a false positive after recent infections or vaccinations with yellow fever virus or Japanese encephalitis. The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.

A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised by if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever. In cases with abdominal pain, in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin. In West Africa, where Lassa is most prevalent, it is difficult for doctors to diagnose due to the absence of proper equipment to perform tests.

The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus. These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection. An ELISA test for antigen and IgM antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate aminotransferase levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid.

The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used including by the World Health Organization's Regional Office for South-East Asia as of 2011. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever. Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected. Grades III and IV are referred to as "dengue shock syndrome".

Control of the "Mastomys" rodent population is impractical, so measures focus on keeping rodents out of homes and food supplies, encouraging effective personal hygiene, storing grain and other foodstuffs in rodent-proof containers, and disposing of garbage far from the home to help sustain clean households . Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person, to avoid contact with blood and body fluids. These issues in many countries are monitored by a department of public health. In less developed countries, these types of organizations may not have the necessary means to effectively control outbreaks.

Researchers at the USAMRIID facility, where military biologists study infectious diseases, have a promising vaccine candidate. They have developed a replication-competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection, test primates have survived lethal challenge, while showing no clinical symptoms.

With the exception of yellow fever vaccine neither vaccines nor experimental vaccines are readily available. Prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections (again, available only as IND).

VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and faceshield or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested, HEPA filter-equipped respirator (such as an N-95 mask), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1,8 meter (six feet) of a VHF patient. Multiple patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants.

Previous methods of diagnosis included HI, complement fixation, neutralization tests, and injecting the serum of infected individuals into mice. However, new research has introduced more efficient methods to diagnose KFDV. These methods include: nested RT-PCR, TaqMan-based real-time RT-PCR, and immunoglobin M antibodies detection by ELISA. The two methods involving PCR are able to function by attaching a primer to the NS-5 gene which is highly conserved among the genus to which KFDV belongs. The last method allows for the detections of anti-KFDV antibodies in patients.

Diagnosis of the oropouche infection is done through classic and molecular virology techniques. These include:

1. Virus isolation attempt in new born mice and cell culture (Vero Cells)

2. Serological assay methods, such as HI (hemagglutination inhibition), NT (neutralization test), and CF (complement fixation test) tests and in-house-enzyme linked immunosorbent assay for total immunoglobulin, IgM, and IgG detection using convalescent sera (this obtained from recovered patients and is rich in antibodies against the infectious agent)

3. Reverse transcription polymerase chain reaction (RT-PCR) and real time RT-PCR for genome detection in acute samples (sera, blood, and viscera of infected animals)

Clinical diagnosis of oropouche fever is hard to perform due to the nonspecific nature of the disease, in many causes it can be confused with dengue fever or other arbovirus illness.

Investigational vaccines exist for Argentine hemorrhagic fever and RVF; however, neither is approved by FDA or commonly available in the United States.

The structure of the attachment glycoprotein has been determined by X-ray crystallography and this glycoprotein is likely to be an essential component of any successful vaccine.

Yellow fever is most frequently a clinical diagnosis, made on the basis of symptoms and the diseased person's whereabouts prior to becoming ill. Mild courses of the disease can only be confirmed virologically. Since mild courses of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea and vomiting six to 10 days after leaving the affected area) is treated seriously.

If yellow fever is suspected, the virus cannot be confirmed until six to 10 days after the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take one to four weeks.

Serologically, an enzyme linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG-titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is considered sufficient indication for yellow fever. Since these tests can cross-react with other flaviviruses, like dengue virus, these indirect methods cannot conclusively prove yellow fever infection.

Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable "post mortem" to confirm the cause of death.

In a differential diagnosis, infections with yellow fever must be distinguished from other feverish illnesses like malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as cause.

Treatment is similar to hepatitis B, but due to its high lethality, more aggressive therapeutic approaches are recommended in the acute phase. In absence of a specific vaccine against delta virus, the vaccine against HBV must be given soon after birth in risk groups.

Measures to reduce contact between the vesper mouse and humans may have contributed to limiting the number of outbreaks, with no cases identified between 1973 and 1994. Although there are no cures or vaccine for the disease, a vaccine developed for the genetically related Junín virus which causes Argentine hemorrhagic fever has shown evidence of cross-reactivity to Machupo virus, and may therefore be an effective prophylactic measure for people at high risk of infection. Post infection (and providing that the person survives the infection), those that have contracted BHF are usually immune to further infection of the disease.

A vaccine is available in the UK and Europe, however in laboratory tests it is not possible to distinguish between antibodies produced as a result of vaccination and those produced in response to infection with the virus. Management also plays an important part in the prevention of EVA.

The "Candid #1" vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990.

"Candid #1" has been applied to adult high-risk population and is 95.5% effective. On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. A vaccination plan is yet to be outlined, but the budget for 2007 allows for 390,000 doses, at AR$8 each (about US$2.6 or €2 at the time). The Institute has the capacity to manufacture, in one year, the 5 million doses required to vaccinate the entire population of the endemic area.

Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005).

The Junín vaccine has also shown cross-reactivity with Machupo virus and, as such, has been considered as a potential treatment for Bolivian hemorrhagic fever.

Biopsies or cultures of a person's tick wound (eschar) are used to diagnose ATBF. However, this requires special culture media and can only be done by a laboratory with biohazard protection. There are more specialized laboratory tests available that use quantitative polymerase chain reactions (qPCR), but can only be done by laboratories with special equipment. Immunofluorescence assays can also be used, but are hard to interpret because of cross-reactions with other rickettsiae bacteria.

Diagnosis of ATBF is mostly based on symptoms, as many laboratory tests are not specific for ATBF. Common laboratory test signs of ATBF are a low white blood cell count (lymphopenia) and low platelet count (thrombocytopenia), a high C-reactive protein, and mildly high liver function tests.

Because of the variability of symptoms, diagnosis is by laboratory testing. Blood samples, nasal swabs and semen can be used for isolation of the virus, detection of the viral RNA by polymerase chain reaction (PCR), and detection of antibodies by ELISA and virus neutralisation tests.

One study has focused on identifying OROV through the use of RNA extraction from reverse transcription-polymerase chain reaction. This study revealed that OROV caused central nervous system infections in three patients. The three patients all had meningoencephalitis and also showed signs of clear lympho-monocytic cellular pattern in CSF, high protein, and normal to slightly decreased glucose levels indicating they had viral infections. Two of the patients already had underlying infections that can effect the CNS and immune system and in particular one of these patients has HIV/AIDS and the third patient has neurocysticercosis. Two patients were infected with OROV developed meningitis and it was theorized that this is due to them being immunocompromised. Through this it was revealed that it's possible that the invasion of the central nervous system by the oropouche virus can be performed by a pervious blood-brain barrier damage.

Prophylaxis by vaccination, as well as preventive measures like protective clothing, tick control, and mosquito control are advised. The vaccine for KFDV consists of formalin-inactivated KFDV. The vaccine has a 62.4% effectiveness rate for individuals who receive two doses. For individuals who receive an additional dose, the effectiveness increases to 82.9%. Specific treatments are not available.

Serological testing is typically used to obtain a definitive diagnosis. Most serological tests would succeed only after a certain period of time past the symptom onset (usually a week). The differential diagnosis list includes typhus, ehrlichiosis, leptospirosis, Lyme disease and virus-caused exanthema (measles or rubella).

Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include a low platelet count, low blood sodium concentration, or elevated liver enzyme levels. Serology testing and skin biopsy are considered to be the best methods of diagnosis. Although immunofluorescent antibody assays are considered some of the best serology tests available, most antibodies that fight against "R. rickettsii" are undetectable on serology tests the first seven days after infection.

Differential diagnosis includes dengue, leptospirosis, and, most recently, chikungunya and Zika virus infections.

Although commercial tests are not readily available, diagnosis can be confirmed by serology-based assays or quantitative PCR by laboratories that have developed assays to perform such identification.

HFRS is difficult to diagnose on clinical grounds alone and serological evidence is often needed. A fourfold rise in IgG antibody titer in a 1-week interval, and the presence of the IgM type of antibodies against hantaviruses are good evidence for an acute hantavirus infection. HFRS should be suspected in patients with acute febrile flu-like illness, kidney failure of unknown origin and sometimes liver dysfunction.

Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. WHO now states that a single dose of vaccination is sufficient to confer lifelong immunity against yellow fever disease." The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler. The World Health Organization (WHO) recommends routine vaccinations for people living in affected areas between the 9th and 12th month after birth.

Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine–associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases.

The Yellow Fever Initiative, launched by WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI Alliance, and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected.

In March 2017, WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil.

A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels.

Detection of viral antibodies on red blood cells is possible.