Crews spent the early hours Friday spraying the pesticides from West 58th Street to West 97th Street between West End Avenue and Central Park.
Trucks were out most of the morning, targeting the surging mosquito population on the Upper West Side and in the park.
Residents who were out for a late stroll say they were caught off guard by what they saw as a threat to their health.
"I've been covering my mouth with my shirt when I see the truck going by," area resident Phil Campo said. "But there's nothing we can do here. They are making us sick more than the mosquitos are making us sick."
The Department of Health says the threat posed by the West Nile virus far exceeds any risks from pesticide exposure. So far this year, 11 city residents have tested positive for the potentially fatal disease.
"We did find elevated virus and counts of mosquitos in this area, so we're treating it," said Mario Merlino, of the health department.
Spraying in the other four boroughs is common, but rare in Manhattan. The only other sprayings happened in Washington Heights in 2003 and 2007, according to city records.
At least 13 human cases of West Nile virus infection have been detected in New York so far this year, including the deaths of two older people in Onondaga and Nassau counties.
The spraying wrapped up around 6 a.m.
WAKE UP WITH EYEWITNESS NEWS! Click here to download the WABC Eyewitness News Alarm Clock app from iTunes. or search WABC or 7online in the app store.
Get Eyewitness News Delivered