Interstate 81 (I-81) is a part of the Interstate Highway System that runs from I-40 at Dandridge, Tennessee, to the Thousand Islands Bridge at Wellesley Island in New York, beyond which the short 2.7-mile (4.3 km) Ontario Highway 137 (Highway 137) links it to Highway 401. In the US state of New York, I-81 extends 183.60 miles (295.48 km) from the Pennsylvania state line southeast of Binghamton to the Canadian border at Wellesley Island northwest of Alexandria Bay. The freeway runs north–south through Central New York, serving the cities of Binghamton, Syracuse, and Watertown. It passes through the Thousand Islands in its final miles and crosses two bridges, both part of the series of bridges known as the Thousand Islands Bridge.

South of Watertown, I-81 closely parallels US Route 11 (US 11), the main north–south highway in Central New York prior to the construction of I-81. 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. From there, the road continues into the province of Ontario as Highway 137, a short route leading north to the nearby Highway 401.

The portion of I-81 in New York was originally developed as the Penn-Can Highway, one of four expressways proposed by the state in 1953. It was added to the Interstate Highway System and designated I-81 in 1957 and constructed in sections over the course of the next decade. The first segment was completed in the mid-1950s, running from Tully to the southern edge of Syracuse. The last piece opened in the late 1960s, linking Marathon to Whitney Point.

I-81 crosses the New York–Pennsylvania border about 11 miles (18 km) southeast of the city of Binghamton. The freeway heads northwest from the state line, running through a valley surrounding the Susquehanna River in the town of Kirkwood. This stretch of I-81 closely parallels US 11, continuing a trend that originally began at I-81's southern terminus in eastern Tennessee. Both roads head across relatively undeveloped areas along the eastern riverbank to the outskirts of Binghamton, where I-81 merges with I-86 in an industrial area east of the city. I-81 and I-86 overlap for five miles (8.0 km), running along the northern edge of the Binghamton suburbs before entering the city itself. About 1.5 miles (2.4 km) north of downtown, the freeway connects to Brandywine Highway, a limited-access road carrying NY 7 through mostly residential areas on the north side of the city.

Just west of the Brandywine Highway junction, I-81 and I-86 cross the Chenango River as they split at a directional T interchange comprising part of an S-curve in I-86 known locally as Kamikaze Curve. While I-86 heads west into the curve, I-81 proceeds northward along the west bank of the river, connecting to US 11 and passing by SUNY Broome on its way into the suburban town of Chenango. Here, I-81 meets the western terminus of I-88 at a junction roughly three miles (4.8 km) north of Binghamton. 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. The route makes its way across a series of hills and valleys for 13 miles (21 km) to the village of Whitney Point, connecting to US 11 and two state routes of regional importance—NY 26 and NY 79—at two exits on the western edge of the community.

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. While US 11 runs across the base of a valley flanking the river, the freeway proceeds along the valley's eastern edge, overlooking the valley road on its way to the Broome–Cortland county line. 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.

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. NY 41 continues west from the exit for a short distance to meet US 11, and the two routes become concurrent for the next five miles (8.0 km). 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. While US 11 and NY 41 continue directly into the city, I-81 bypasses it to the northeast. As such, it crosses only moderately developed areas on the periphery of Cortland. The road connects to downtown Cortland by way of an exit with NY 13, a north–south route serving most of Central New York. Near the exit, the Tioughnioga River splits into two branches, with NY 13 following the east branch to the northeast and I-81 proceeding westward along the west branch.

North of downtown Cortland, I-81 makes a 90-degree turn to the north, matching a similar curve in the course of the nearby river. This track brings the freeway to the suburban village of Homer, which I-81 connects to via exit 54. The trumpet interchange feeds into a long east–west ramp linking the highway to the parallel US 11, NY 41, and NY 281, another parallel road farther west. NY 41 leaves US 11 in Homer, and I-81, US 11, and NY 281 proceed slightly northeastward across a low-lying, undeveloped area in an otherwise hilly region of Cortland County. 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. They meet one final time across the county line near the village of Tully, where NY 281 ends as I-81 intersects NY 80 and NY 11A. The west branch of the Tioughnioga River also terminates here, flowing into Tully Lake at the county line.