At Watertown, US 11 turns northeastward to head across New York's North Country region while I-81 continues on a generally northward track to the Canadian border.

The freeway heads northwest from the state line, running through a valley surrounding the Susquehanna River in the town of Kirkwood.

Continuing on, the freeway intersects US 11 a second time before leaving the banks of the Susquehanna River and proceeding generally northwestward into increasingly rural areas of the Southern Tier.

[3] Continuing on, I-81 begins to follow the Tioughnioga River, a tributary of the Susquehanna, as it bypasses the nearby village of Lisle to the east.

Both routes cross the border at points just yards apart, beginning their transition from the Southern Tier region to Central New York.

About two miles (3.2 km) from the county line, I-81 encounters the village of Marathon, situated inside the river valley at the junction of US 11 and NY 221.

The freeway connects to the latter at an interchange just east of the village center before heading northwestward for 11 miles (18 km) across a series of moraines in another prolonged rural stretch.

Along the way, I-81 passes between the Tuller Hill and Hoxie Gorge state forests, located near Messengerville on the western and eastern sides of the highway, respectively.

[3] The rural, northwestward trend ends west of the village of McGraw at a junction with NY 41, the primary east–west (signed north–south) road through the community.

I-81, US 11, and NY 41 all head westward from this point, passing a handful of scattered businesses to reach the eastern edge of the nearby city of Cortland.

Just south of the Onondaga County line, I-81 directly meets NY 281 as it crosses from the western side of the freeway to the eastern edge.

At this point, the forests that had lined both roads give way to the dense residential neighborhoods that comprise the city's southern half.

Roughly three miles (4.8 km) south of Downtown Syracuse, I-81 meets with I-481, an alternate route of I-81 bypassing the city to the east.

I-81 itself proceeds due north toward downtown on an embankment, running alongside the New York, Susquehanna and Western Railway (NYSW) and passing adjacent to Oakwood Cemetery.

[6] Farther north, the density of the commercial districts adjacent to the highway continue to increase as the road enters Downtown Syracuse.

For roughly a half-mile (0.80 km), I-81 heads east–west, running alongside I-690 and connecting to the highway by way of a series of closely spaced ramps.

[7] The cut eventually brings the freeway to the southeastern tip of Onondaga Lake, where I-81 ascends in elevation once again at a network of interchanges with NY 370 and a handful of nearby streets.

North of the rail overpass, the road finally returns to ground level as it heads northeastward through Syracuse's residential northern suburbs.

Just north of the junction with I-481 and NY 481, the freeway passes east of the former Penn-Can Mall, the largest commercial parcel in the area.

North of here, US 11 begins to closely parallel I-81 once again, rejoining the highway's vicinity after following an erratic alignment through Syracuse.

[3] On the opposite riverbank, I-81 initially runs past a line of lakefront houses and cottages; however, it soon enters a large marshy area named Big Bay Swamp.

From here to Watertown, I-81 loosely parallels Lake Ontario, located about seven miles (11 km) to the west and more closely followed by NY 3.

[8][9] Past Sandy Creek, I-81 proceeds into Jefferson County, where it continues to travel across rural, undeveloped areas with only gentle elevation changes.

[3] The long, continuous bridge span between the U.S. mainland and Wellesley Island (one of the archipelago's largest) is one of the few remaining two-lane stretches left on the Interstate Highway System.

One of the four proposed highways closely followed US 11, beginning in Binghamton and proceeding generally northward through Central New York to the Canadian border north of Watertown.

[17] I-81 was opened to traffic from the Pennsylvania state line north to NY 17 in Kirkwood in mid-1961,[18][19] and the piece linking Pamelia to the Canadian border was completed on September 29, 1965.

[25] The portion for road in Binghamton, nicknamed the Kamikaze Curve due to its hazardous design, was demolished and replaced as part of a project undertaken from 2014 to December 2020.

In 2001, Syracuse Common Councillor Van Robinson called for the removal of some elevated portions of I-81 that were blocking Upstate Medical University.