Otisco is a town in Onondaga County, New York, United States.

Otisco is in the southwestern part of the county, situated at the northern edge of the Appalachian Highlands, where an escarpment declines to the Lake Ontario plain and the city of Syracuse five miles to the north.

The name "Otisco" may have been derived from the Iroquois name for Nine Mile Creek, Us-te-ke, meaning "bitter-nut-hickory".

A short part of US Route 20 crosses the northeastern corner of the town.

18.9% of all households were made up of individuals, and 6.3% had someone living alone who was 65 years of age or older.