It extends for 23.97 miles (38.58 km) from an intersection with NY 417 in the city of Salamanca to a junction with U.S. Route 62 (US 62) in the hamlet of Dayton.

In between, the route traverses isolated and undeveloped areas of the county, save for the villages of Little Valley and Cattaraugus.

[4] It initially heads northward on the city-maintained Center Street[5] through a commercial section of Salamanca; however, the surroundings become more residential after the route crosses the Allegheny River.

[5] Now in the surrounding town of Salamanca, NY 353 continues northward on Center Street into a large, mostly undeveloped valley surrounding Little Valley Creek, where the route passes east of Bucktooth Hill and west of Lindell Lookout.

[4] Past State Street, NY 353 heads through the valley as an unnamed road,[4] paralleling the former right-of-way of an Erie–Lackawanna rail line (now the Pat McGee Trail)[6] into the town of Little Valley and the small hamlet of Elkdale, where the highway passes a local country club and intersects the North Country Trail.

North of Elkdale, the route curves to the northwest, matching a similar turn in the path of the creek valley.

The concurrent routes, known as Rock City Street, head into the village's central business district, where NY 242 splits off to the southwest.

After 2.5 miles (4.0 km), the route makes a sharp turn to the northwest, paralleling the New York and Lake Erie Railroad into the hamlet of Dayton, where NY 353 comes to an end at an intersection with US 62.