The eastern portion of NY 421 was built in the 1920s under the terms of a 1923 law authorizing the construction of a highway leading from modern NY 30 north to Warren Point. This road was completed in 1925. NY 421 was assigned to the entirety of the north–south highway . The roadway connecting Horseshoe Lake to Tupper Lake was built and became part of NY 421 by 1968. NY 421's former routing to Warren Point remained a state highway up through 1999, when a bill permitting the New York State Department of Transportation (NYSDOT) to remove it from the state highway system was signed into law.