The street owes its name to Hendrik Doyer, an 18th-century Dutch immigrant who bought the property facing the Bowery in 1791 and operated a distillery where the post office is now sited. From 1893 to 1911, Doyers Street was the site of the first Chinese language theater in New York City. The theater was converted into a rescue mission for homeless from the Bowery.

Early in the century, the bend in the street became known as "the Bloody Angle" because of numerous shootings among the Tong Gangs of Chinatown that lasted into the 1930s. The street was ideal for street battles not just because of its angle but also because of the tunnels that connected the buildings. Hatchets were frequently used, leading to the creation of the expression, "hatchet man." According to law enforcement officials, more people died violently at the "Bloody Angle" than at any other street intersection in the United States.