The southern terminus of the route is located at Interstate 690 (I-690) exit 3 near the interchange between I-690 and the New York State Thruway (I-90) in Van Buren, northwest of Syracuse.

When the route was originally assigned as part of the 1930 renumbering of state highways in New York, it extended southward into downtown Syracuse.

Around 1931, a suffixed spur of NY 48, New York State Route 48A was designated as an alternate from Oswego to the town of Minetto.

NY 48 begins at I-690 exit 3 just west of the Geddes town line in Van Buren, Onondaga County.

[3] Further north in Lysander, NY 48 crosses the CSX Transportation-owned Baldwinsville Subdivision before turning to the northeast as it passes through the hamlet of Wrights Corners and entering Oswego County.

[3] NY 48 is city-maintained within the cities of Fulton and Oswego; the rest of the highway is maintained by the New York State Department of Transportation (NYSDOT).

[5][6] In the 1930 renumbering of state highways in New York, NY 48 was assigned to a previously unnumbered roadway between downtown Syracuse and Oswego.

[8][9] The portion of the New York State Thruway from Rochester east to the Westmoreland hamlet of Lowell opened on June 24, 1954.

Other areas of State Fair Boulevard (NY 48) were upgraded into limited-access highways, including at Thruway exit 39 and in downtown Syracuse.

[13] Following the removal of NY 48 south of the Thruway, the portion of State Fair Boulevard from the Syracuse city line north to I-690 exit 5 in Geddes became CR 80.