Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.

No drug is currently approved for the treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.

Badi Mata is a female deity worshiped by some tribes in India, like the Saharia, Kamar etc. The worshipers believe that her wrath causes people to suffer from the small pox disease. The worshipers sacrifice goats to appease her.

Another similar deities are: Chhoti Mata who is associated with chicken pox and Sendri Mata who is associated with measles.

The earliest procedure used to prevent smallpox was inoculation (known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty. If successful, inoculation produced lasting immunity to smallpox. Because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.

Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire, writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. In 1796, Edward Jenner, a doctor in Berkeley, Gloucestershire, rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine, from the root word "vacca", which is Latin for cow. The procedure was much safer than variolation, and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by vaccinia virus. Vaccinia is in the same family as cowpox and variola, but is genetically distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not known. According to Voltaire (1742), the Turks derived their use of inoculation to neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years".

The current formulation of smallpox vaccine is a live virus preparation of infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) a number of times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar.

The antibodies induced by vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination, and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated. Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years prior to infection. By contrast, 52 percent of unvaccinated persons died.

There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body, and to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia).

Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972, and was abandoned in most European countries in the early 1970s. Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination). By 1986, routine vaccination had ceased in all countries. It is now primarily recommended for laboratory workers at risk for occupational exposure.

One theory (Kristina Palacio) explains "usog" in terms of child distress that leads to greater susceptibility to illness and diseases. There are observations that a stranger (or a newcomer or even a visiting relative) especially someone with a strong personality (physically big, boisterous, has strong smell, domineering, etc.) may easily distress a child. Thus, the child is said to be "overpowered" or "nauusog" and thus may feel afraid, develop fever, get sick, etc.

In "usog", the child's distress is the consequence of the child's failure to adapt to change. It is, in medical terms, the consequence of the disruption of homeostasis through physical or psychological stimuli brought about by the stranger. Technically, the condition results from the child-environment interaction that leads the child to perceive a painful discrepancy, real or imagined, between the demands of a situation on the one hand and their social, biological, or psychological resources on the other. The stressful stimuli to the child may be mental (stranger is perceived as a threat, malevolent or demanding), physiological (loud and/or high-pitched voice of the stranger that is hurting to the child's eardrum; strong smell of the stranger that irritates the child's nasal nerves), or physical (stranger has heavy hands or is taking up too much space).

The stranger's act of gently placing his finger with his saliva to the child's arm, foot, or any particular part of the child's body, could make him more familiar to the child, and thus, reduce if not remove the stress. As the stranger keeps gently saying, "Pwera usog... pwera usog...," the child is made to feel and assured that he means no harm. The "usog" is said to be counteracted because the child is prevented from succumbing to an illness since the child is no longer in distress. Children or even adults who are shy or have weak personalities are more susceptible to "usog" in accordance with observations and theory. Some have observed that at times even praising a shy child by a visiting relative caused an "usog".

The saliva from the stranger, granted that he or she is healthy and consistent with his or her oral hygiene, is relatively clean and contains enough antimicrobial compounds such as lactoferrin, lactoperoxidase, and secretory immunoglobulin A which can help clear pathogens from the child and benefit the child against infection. Furthermore, human saliva has opiorphin, a newly researched pain-killing substance. Initial research with mice shows the compound has a painkilling effect of up to six times that of morphine. It works by stopping the normal breakdown of natural pain-killing opioids in the spine, called enkephalins. Opiorphin in human saliva is a relatively simple molecule, and the child's immune system may trigger a biochemical cascade (complement system) to produce other stress-reducing compounds.

Usog can also, though less commonly, affect adults, and it may induce vomiting and stomach ache rather than fever. Supposedly, it can be prevented by stopping a stranger or visitor from greeting the person.

Unlike "lihi", however, usog is not yet medically accepted. More than the superstitious folks, researchers dealing with Filipino Psychology say they have observed this phenomenon with regularity and suggest that this be added to the Psychiatric Disorders Handbook DSM-V.

Usog or balis is a topic in psycho-medicine in Filipino Psychology (but considered just as a Filipino superstition in Western Psychology) where an affliction or psychological disorder is attributed to a greeting by a stranger, or an evil eye hex. It usually affects an unsuspecting child, usually an infant or toddler, who has been greeted by a visitor or a stranger.

In some limited areas, it is said that the condition is also caused by the stranger having an evil eye or "masamang mata" in Tagalog, lurking around. This may have been influenced by the advent of the Spaniards who long believed in the "mal de ojo" superstition.

Once affected, the child begins to develop fever, and sometimes convulsions. Supposedly, the child can be cured by placing its clothing in hot water and boiling it. In most other places, to counter the effects of the "usog" the stranger or newcomer is asked to put some of his or her saliva on the baby's abdomen, shoulder or forehead before leaving the house. The newcomer then leaves while saying: ""Pwera usog... pwera usog..."" The saliva is placed on the finger first, before the finger is rubbed on the baby's abdomen or forehead. The stranger is never to lick the child. The practice is that the stranger or visitor is asked to touch his or her finger with saliva to the child's body, arm or foot (""lawayan"") to prevent the child from getting overpowered (""upang hindi mausog"").

Running amok, sometimes referred to as simply amok or gone amok, also spelled amuk, from the Malay language, is "an episode of sudden mass assault against people or objects usually by a single individual following a period of brooding that has traditionally been regarded as occurring especially in Malay culture but is now increasingly viewed as psychopathological behavior". The syndrome of "Amok" is found in the "Diagnostic and Statistical Manual of Mental Disorders" (DSM-IV TR). The phrase is often used in a less serious manner when describing something that is wildly out of control or causing a frenzy (e.g., a dog tearing up the living room furniture might be termed as "running amok".)

In 1849, amok was officially classified as a psychiatric condition based on numerous reports and case studies that showed the majority of individuals who committed amok were, in some sense, mentally ill. The modern DSM-IV method of classification of mental disorders contains two official types of amok disorder; beramok and amok. Beramok is considered to be the more common of the two and is associated with the depression and sadness resulting from a loss and the subsequent brooding process. Loss includes, but is not limited to, the death of a spouse or loved one, divorce, loss of a job, money, power, etc. Beramok is associated with mental issues of severe depression or other mood disorders. Amok, the rarer form, is believed to stem from rage, insult, or a vendetta against a person, society, or object for a wide variety of reasons. Amok has been more closely associated with psychosis, personality disorders, bipolar disorder, and delusions.