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.

Where mammalian tick infection is common, agricultural regulations require de-ticking farm animals before transportation or delivery for slaughter. Personal tick avoidance measures are recommended, such as use of insect repellents, adequate clothing, and body inspection for adherent ticks.

When feverish patients with evidence of bleeding require resuscitation or intensive care, body substance isolation precautions should be taken.

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.

Since the 1970s, several vaccine trials around the world against CCHF have been terminated due to high toxicity.

, the only available and probably somewhat efficacious CCHF vaccine has been an inactivated antigen preparation then used in Bulgaria. No publication in the scientific literature related to this vaccine exists, which a Turkish virologist called suspicious both because antiquated technology and mouse brain were used to manufacture it.

More vaccines are under development, but the sporadic nature of the disease, even in endemic countries, suggests that large trials of vaccine efficacy will be difficult to perform. Finding volunteers may prove challenging, given growing anti-vaccination sentiment, resistance of populations to vaccination against contagious diseases. The number of people to be vaccinated, and the length of time they would have to be followed to confirm protection would have to be carefully defined. Alternatively, many scientists appear to believe that treatment of CCHF with ribavirin is more practical than prevention, but some recently conducted clinical trials appear to counter assumptions of drug efficacy.

In 2011, a Turkish research team led by Erciyes University successfully developed the first non-toxic preventive vaccine, which passed clinical trials. As of 2012, the vaccine was pending approval by the US FDA.

Since the Ebola epidemic, the WHO jumpstarted a "Blueprint for Research and Development preparedness" on emerging pathogens with epidemic potential, against which there are no medical treatments. CCHF was the top priority on the initial list from December 2015, and is second as of January 2017.