The route was assigned in the mid-1920s to an alignment extending from Claverack to Nassau via Ghent. It was extended north to Troy as part of the 1930 renumbering of state highways in New York and rerouted south of Ghent to serve Hudson . Originally, NY 66 directly served Averill Park via modern County Route 45 (CR 45) and part of NY 43; however, it was realigned in 1980 to bypass the hamlet to the northeast. The segment of NY 66 between Sand Lake and US 20 was part of Route 21, an unsigned legislative route, in the early 1920s.