Its western terminus is located at a junction with NY 175 in the city of Syracuse in Onondaga County, from which it actually runs in a north–south direction for 20 miles (32 km).

NY 80 leaves to the southwest shortly after to serve South Onondaga and intersect U.S. Route 20 at Lords Corners.

Outside of New Berlin, NY 80 heads northeast to Edmeston, where it rejoins the routing of the Second Great Western Turnpike at an intersection with CR 20.

Shortly after entering Cooperstown, the two routes split as NY 28 turns south at Chestnut Street, following the roadway out of the village toward Oneonta.

Near the northern tip of the lake in Springfield, NY 80 intersects US 20 (the former Cherry Valley Turnpike) for the second time, where it becomes signed as a north–south route.

The route continues northward, although the progression becomes more northeasterly as it crosses into the rural southeastern corner of Herkimer County.

[4] Upon entering Montgomery County, NY 80 heads east to Fort Plain, a village located on the Mohawk River (here serving as the path of the Erie Canal), and becomes Main Street.

[4] The routing of most of modern NY 80 between Sherburne and Cooperstown was originally part of the Second Great Western Turnpike, an early toll road established in 1801.

While what is now NY 80 dips south to serve New Berlin, the turnpike bypassed the settlement to the north, favoring a direct alignment between Columbus and Edmeston.

[7] When the first set of posted routes in New York were assigned in 1924, none of the former turnpike was incorporated into the system; however, a road between Cooperstown and Springfield along the western edge of Otsego Lake was designated as part of NY 28.

[8] By 1926, a small segment of the ex-Second Great Western Turnpike between Edmeston and West Burlington was signed as part of NY 44.

[10] From Sherburne to Columbus and from West Burlington to Cooperstown, NY 80 utilized a previously unnumbered roadway that roughly followed the former alignment of the Second Great Western Turnpike.