Upon crossing I-81 in North Syracuse, I-481 continues northwest to Fulton and Oswego as New York State Route 481 (NY 481).

Immediately crossing under NY 173, I-481 proceeds eastward alongside Rock Cut Road (unsigned County Route 103 [CR 103]), which meets the freeway at exit 83 heading east.

I-481 crosses out of Syracuse and into the town of Onondaga, paralleling Rock Cut Road into Clark Reservation State Park.

The Interstate Highway makes a bend to the northeast, crossing over tracks used by the New York, Susquehanna and Western Railway and entering exit 85, which connects to Jamesville Road (CR 7).

After the junction, I-481 continues bending to the northeast, crossing the west end of Old Erie Canal State Park and east of White Chapel Memory Gardens before entering a large interchange with the eastern terminus of I-690.

Just north of the interchange, I-481 crosses over NY 290 (Manlius Center Road) and CSX Transportation's DeWitt Yard.

The freeway continues northeast, crossing over East Taft Road (CR 18) in DeWitt before bending northwest into the town of Cicero.

From the New York State Thruway (I-90) in DeWitt[2] southwest to I-81 in the south end of Syracuse, the highway was originally designated as I-281.