It runs in a roughly north–south direction for 6.35 miles (10.22 km) through the southwestern and central parts of Amherst from an interchange with I-290 north of Buffalo to an intersection with New York Route 263 (NY 263, named Millersport Highway) south of Lockport.

It generally parallels Sweet Home Road (unsigned NY 952T) to exit 1, a northbound-only interchange providing access to Audubon Parkway by way of a two-lane connector to the campus.

From here, I-990 gradually bends northeastward, leaving the vicinity of the campus and entering a partial cloverleaf interchange (exit 2) connecting to Sweet Home Road.

[5] The Interstate Highway continues to turn to the northeast as it heads away from exit 2, crossing over Ellicott Creek and Dodge Road (County Route 45).

I-990 expands to six lanes just as it enters the nearby exit 3, which connects to Dodge Road and the northern end of the Audubon Parkway.

The freeway briefly runs eastward from the junction, paralleling Dodge Road into the hamlet of Getzville, where the expressway passes over NY 270 (Campbell Boulevard).

Just after the NY 270 crossing, I-990 bends northward once again and enters exit 4, a diamond interchange with North French Road (CR 299).

[7] While the outer belt proposal was mostly dropped, the plans to build the Lockport Expressway gained traction in January 1979 when the 4.2-mile (6.8 km) portion between I-290 and North French Road was added to the Interstate Highway System and designated as I-990.