West Nile virus was first isolated from a feverish adult woman in the West Nile District of Uganda in 1937. The ecology was characterized in Egypt in the 1950s. The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France in the early 1960s.

The first appearance of West Nile virus in North America in 1999 with encephalitis reported in humans and horses, and the subsequent spread in the United States may be an important milestone in the evolving history of this virus. The US outbreak began in the New York City area, and the virus is believed to have entered in an infected bird or mosquito. Since the first North American cases in 1999, the virus has been reported throughout the United States and Canada east of the Rocky Mountains. There have been human cases and horse cases, and many birds — especially crows and other corvids — are infected. Corvids die of the disease more often than other species of birds so the presence of dead crows is an early indicator of the arrival of the virus.

A very high level of media coverage through 2001/2002 raised public fears of West Nile virus, even though common diseases such as influenza take far more lives each year. This disproportionate coverage is most likely the result of the novelty of the disease and the successive announcements of the disease's initial appearance in new areas.

Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying that the detrimental health effects of spraying outweigh the relatively few lives which may be saved, and that there are more environmentally friendly ways of controlling mosquitoes. There are also questions about the effectiveness of insecticide spraying because mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern U.S., Culex pipiens, is a canopy feeder.