The part of the route north of East Aurora follows a generally north–south alignment to an intersection with NY 18 in the Niagara County town of Newfane (at the hamlet of Olcott), just south of the Lake Ontario shoreline.

[3] After the hamlet of Wethersfield, NY 78 continues southwest, crossing through rural farms as a two-lane roadway, intersecting with the southern terminus of CR 57 (Poplar Tree Road).

[3] Now in the town of Java, NY 78 uses the right-of-way once used by CR 11 northbound, winding past several farms as it proceeds northward.

After an intersection with Elm Road, NY 78 regains the Main Street moniker, crossing into the town of Sheldon and into the hamlet of Strykersville.

[3] After CR 35, NY 78 bends northwest out of Strykersville, crossing into the rural sections of Sheldon surrounding the hamlet.

The two-lane rural roadway remains the same for several miles to the northwest, crossing an intersection with CR 382 (Hunters Creek Road).

The routes remain a two-lane residential street for a distance, intersecting with CR 383 (Reiter Road) as it winds west.

The routes slowly becomes commercial once again, passing a large industrial building before entering an at-grade interchange with CR 574 (Jamison Road).

The route remains a two-lane residential road for a distance, soon bending further northwestward into the town of West Seneca.

[3] US 20 and NY 78 proceed northward along Transit Road, remaining a major commercial thoroughfare street serving the eastern suburbs of Buffalo with limited pockets of residential along its run.

A short distance later, the routes cross over Cayuga Creek and enter an intersection with the western terminus of NY 130 (Broadway).

At this junction, NY 78 continues north on Transit Road, while US 20 turns east onto Broadway through the village of Depew.

Continuing north through Depew, NY 78 intersects with the eastern terminus of CR 316 (George Urban Boulevard).

Continuing north through Depew, NY 78 and Transit Road remain the four-lane commercial boulevard through the center of town, passing numerous businesses.

NY 78 and Transit Road north of I-90 continues as the town line of Amherst to the west and Lancaster to the east.

[3] North of Wehrle Drive, Transit Road widens to six and then eight lanes wide as it passes through a dense commercial shopping distance along the Amherst-Clarence town line until NY 5 (Main Street).

The route condenses back to six lanes along the Eastern Hills Mall in Clarence, entering an intersection with a feeder road that connects to NY 324 (Sheridan Drive).

Soon entering the hamlet of Swormville, NY 78 and Transit Road remain a four-lane commercial boulevard through Amherst and Clarence.

[3] After crossing Tonawanda Creek, NY 78 and Transit Road enter the town of Lockport as a four-lane boulevard.

The route remains four lanes, but becomes a boulevard through wide fields for a distance, passing runway 28 of North Buffalo Suburban Airport.

Now in the town of Pendleton for a short distance, NY 78 and Transit Road cross through a long stretch of fields, becoming a commercial boulevard to the north.

The route becomes a two-lane residential street, passing Dolan Park and turning north on Lake Avenue.

[3] Crossing back into the town of Lockport, NY 78 continues north along Lake Avenue, intersecting with CR 31 (Old Niagara Road).

A short distance to the north, it enters the hamlet of Highland Park, winding northward as a two-lane commercial roadway.

Still in the town of Newfane, NY 78 proceeds northwest as a four-lane (quickly changing to two-lane) residential street.

[3] Through the hamlet of Newfane, NY 78 winds northwest along Eighteenmile Creek, intersecting with CR 137 (Ewings Road).

Paralleling Eighteenmile Creek out of Newfane, the route intersects with CR 104 (Ide Road)'s eastern terminus.

After crossing the eastern terminus of CR 52 (Wilson–Burt Road), NY 78 continues north through the town of Newfane, entering the hamlet of Burt.

This intersection serves as the northern terminus of NY 78, while the right-of-way continues north as Lockport Street, which terminates at the shore of Lake Ontario.