Retaining the commercial design, NY 281 crosses over the abandoned Lehigh Valley railroad line, passing west of SUNY Cortland.

[4] After CR 111, NY 281 continues northeast as a four-lane roadway through Cortlandville, crossing into the city of Cortland for a short distance near St. Mary's Cemetery.

The route remains residential for a distance, passing west of Cortland Country Club.

The route passes east of Glenwood Cemetery, intersecting with NY 90 (Cayuga Street).

[4] NY 281 continues north through Homer, passing a stretch of residences before an intersection with CR 102 (Cold Brook Road).

[4] In Preble, NY 281 proceeds northeast at a fork that serves as the southern terminus of CR 108A (Steger Road).

A short distance to the north, the route enters the hamlet of Preble, with NY 281 becoming a two-lane residential street.

After I-81, NY 281 continues northeast for a short distance through Preble, turning north on a parallel of the northbound lanes of I-81.

[4] Now paralleling a railroad line, NY 281 intersects with CR 106 (Song Lake Crossing Road).

[12] On March 30, it was announced that the decision to renumber NY 281 was withdrawn citing massive opposition.