The highway runs from the Pennsylvania state line south of Binghamton in Broome County, New York, to the Vermont state line east of Hoosick in Rensselaer County, where it continues as Vermont Route 9 (VT 9).

Portions of the highway route near the cities of Binghamton, Schenectady, and Troy date back to the early 19th century.

From Corbettsville northward, NY 7 becomes the riverside highway, following the river (as well as U.S. Route 11 or US 11 and I-81 on the opposite bank) through Conklin to eastern Binghamton, where it indirectly connects to US 11 via a bridge over the Susquehanna.

Immediately north of Binghamton in Port Dickinson, NY 7 merges with I-88 across the Chenango River from the western terminus of I-88 at I-81.

NY 7, however, passes over the Thruway with no connection and heads east into Rotterdam as Duanesburg Road.

In the center of the community, NY 7 turns east onto Curry Road, remaining on the roadway to an interchange with I-890 adjacent to the Schenectady Albany county line.

At the end of the arterial in eastern Schenectady, NY 7 becomes the at-grade Troy–Schenectady Road as it heads along the south bank of the Mohawk River into Albany County.

Shortly after entering the county and the Town of Colonie, NY 7 leaves the river and progresses southeast toward the hamlet of Latham.

Soon after passing the Albany International Airport and prior to entering the center of Latham, NY 7 meets I-87 (the Adirondack Northway) at exit 6.

At exit 7, NY 7 separates from the Adirondack Northway and continues east on a five-lane, limited-access freeway known locally as "Alternate Route 7".

The route connects to US 9 and I-787 / NY 787 by way of interchanges prior to crossing over the Hudson River and into Troy over the Collar City Bridge.

[7] Portions of modern NY 7 between Binghamton and Central Bridge were part of the Susquehanna Valley Route Auto trail.

Most of modern NY 7 was first defined in the 1909 Highway Law (amended in 1911)[9] as State Route 7, which was designated from the Pennsylvania state line at Binghamton town to Harpursville, then along the Susquehanna Valley through Oneonta to the town of Schoharie.

The portion of modern NY 7 continuing northeast from the town of Schoharie to Schenectady was part of State Route 7A.

Prior to 1930, NY 7 began at Court Street in Binghamton and followed Chenango Street north into Fenton, where it turned east and continued through Port Crane to the Colesville hamlet of Sanitaria Springs.

[17] The Brandywine Highway, a four-lane arterial through Binghamton and Port Dickinson, opened to traffic c. 1961 as a realignment of NY 7.

[18][19] The portion of NY 7 between Port Dickinson and Sanitaria Springs was relocated onto a new limited-access highway between 1968 and 1973.

Here, the route split from I-890 and continued to the junction of Union Street and Rosendale Road east of the city by way of a new arterial.

[1][22] Prior to the creation of the modern reference route system, Altamont Avenue was designated as NY 951.

[30] In 1981, the Collar City Bridge was built, connecting Green Island with Troy in the Capital District.

NY 28 was rerouted to follow its current alignment between Main Street south of Oneonta and D.K.

The current New York State Route 7B (NY 7B) designation is a 3.74-mile (6.02 km) spur in the Broome County towns of Fenton and Colesville.