Once reaching the village of Silver Creek it briefly overlaps US 20 until entering Erie County at the Cattaraugus Reservation and NY 438 where the roads once again split.

Near the northern edge of the city, NY 5 begins to ascend onto an elevated roadway as it connects to Ridge Road and the Buffalo and Erie County Botanical Gardens by way of an interchange.

[10] A short distance past the city line, NY 5 passes over the Union Ship Canal on a span of the elevated road known as the Father Baker Bridge.

Both the service road and NY 5 run parallel to Lake Erie until the northern end of the Buffalo Outer Harbor.

Here, the frontage roads end while NY 5 turns to the northeast, crossing the Buffalo River on the bridge called The Skyway, and entering downtown.

On the north bank, the Skyway returns to a northerly routing as it passes KeyBank Center, located directly to the east, and Buffalo and Erie County Naval & Military Park, situated to the west, and meets I-190 at exit 7.

Past the interchange, the Skyway ends and the route descends in elevation, becoming an at-grade roadway once more at Church Street in the shadow of Buffalo City Hall.

At a rural intersection controlled by single-head flashing traffic signals west of Avon, NY 5 meets US 20 for the second time.

The routes embark on a second concurrency, merging onto the right-of-way of NY 5 as they cross the Genesee River and enter both the town and village of Avon.

[10] US 20 and NY 5 become West Main Street upon entering the village, underscoring the road's status as the primary east–west highway through the town.

[10] In the centre of Avon, West Main feeds into Park Place, a large traffic circle providing access to two local streets from US 20 and NY 5.

Continuing, the road intersects several county routes over the next four miles (6  km) before becoming West Main Street once more, this time for the village of Lima.

Exiting the hamlet, US 20 and NY 5 head through another area dominated by open land, intersecting Elton Road before passing seamlessly into East Bloomfield.

Across the town line in Hopewell a quarter-mile to the east, a third plaza, anchored by Runnings, formerly a Walmart, dominates the northeast corner of CR 10 and Eastern Boulevard.

[15] Past the split, NY 5 continues east through Onondaga and Madison counties, passing Fayetteville, Chittenango, and Canastota before entering the vicinity of Oneida.

It closely parallels the Thruway to Herkimer, where NY 5 moves slightly northward through the centre of the village, becoming State Street, while I-90 crosses the Erie Canal and goes south for a short distance.

While rudimentary roads were laid out following the Mohawk River, there were no major land routes west of Fort Schuyler (present-day Utica), except for an old east–west Iroquois trail that was a simple footpath.

As planned, it generally followed the old Iroquois trail through Oneida, Manlius, Onondaga Valley (south of modern Syracuse), Skaneateles, Auburn, Seneca Falls, Geneva, and Canandaigua[17] before ending at the Genesee River.

[16] By the end of the 18th century, while the Genesee Road had been greatly improved and saw heavy traffic, many portions were still substandard and some sections had still not been completed.

[17][18] Partly because of this, and also because of the success of the Lancaster Turnpike in Pennsylvania, the state outsourced the task of improving and maintaining the Genesee Road to a private company.

[21] This branch left the original turnpike east of Seneca Falls and crossed more level terrain through Elbridge, Geddes, and Fayetteville before rejoining the old path at Chittenango.

[17][19] As the city of Syracuse developed, traffic patterns changed and the northern branch route became more heavily used than the original road.

[21] The construction and opening of the Erie Canal in 1825 along the same alignment as the Albany to Buffalo route began to eat away at the revenues of these turnpike companies.

[17][19] The improvement of the road from Buffalo southwest to Pennsylvania in the mid-19th century soon allowed for continuous travel across the entire state of New York.

The Albany to Buffalo portion of the Yellowstone Trail, which ran through the cities of Syracuse and Utica, was assigned the number NY 5A.

The portion of the Yellowstone Trail southwest of Buffalo and east of Albany became part of NY 5, which bypassed Syracuse and Utica to the south.

This truncated both ends of NY 5 to Athol Springs (south of Buffalo in the town of Hamburg) in the west, and to Albany in the east.

[27] Southwest of Buffalo, Southwestern Boulevard, an alternate route of US 20 between Irving and Big Tree (east of Athol Springs) became NY 20B.

[28] Further southwest, another alternate route of US 20 between the Pennsylvania line and Silver Creek, running along the shore of Lake Erie, was designated as NY 20A.

At the river, the new roadway broke from Fuhrmann and continued directly into downtown, returning to grade level two blocks south of Niagara Square.