Red paint was splashed on the base of the Theodore Roosevelt statue on the steps of the American Museum of Natural History, police say.
The vandalism was discovered at about 7 a.m. Thursday.
The bronze statue by James Earle Fraser depicts the former president and New York police commissioner on horseback flanked by an African and a Native American. It was erected in 1939.
The incident comes after a city commission was formed on what to do with statues and monuments seen to have oppressive historical connotations.
Last month, a statue of Christopher Columbus in Central Park was vandalized with graffiti saying "hate will not be tolerated" and his hands were painted red.