From 1911 to 1921, the north–south section of modern NY 251 near Scottsville was part of Route 15, an unsigned legislative route assigned by the New York State Legislature. The first portion of what is now NY 251 to receive a posted designation was the segment east of NY 64 in Mendon, which was part of the signed NY 15 from 1924 to 1930. In the 1930 renumbering of state highways in New York, NY 251 was assigned to an alignment extending from Gates to Victor via Scottsville, utilizing modern NY 386 north of Scottsville and its current alignment east of the village. NY 251 was truncated to begin at NY 383 in Scottsville on July 1, 1977, at which time the former routing of NY 251 between Scottsville and Gates became part of an extended NY 386.