The route follows a generally northwest–southeast alignment between the two points, passing along the north shore of Oneida Lake and directly serving the city of Rome.

Route 49 leaves Central Square and heads southeast toward both Constantia and the Oneida Lake shoreline.

[4] East of the hamlet of Constantia, the highway begins to parallel the north shore of Oneida Lake.

After 2.5 miles (4.0 km) of rural surroundings, the route passes out of Rome and into Verona upon traversing Wood Creek.

The road continues south to the community of New London, where it intersects and joins NY 46 on the north bank of the Erie Canal.

As the expressway curves back to the east, it crosses a railroad spur leading to the former Griffiss Air Force Base at-grade, a rare occurrence on limited-access highways.

Route 49 then meets NY 825, the vehicular southern entrance to the ex-base, by way of an interchange before leaving the Rome limits.

[4] Just east of Cavanaugh Road, the median of the expressway widens as it heads toward the New York State Thruway (I-90).

The rash of incidents, coupled with a two-car collision that killed five people in December 1953, led the state Department of Public Works to investigate potential safety issues with the road.

Although the study attributed virtually all of the accidents to poor driver judgment, it also noted that the corridor's traffic volume had exceeded the road's capacity.

The highway connected to NY 12C and River Road at Carey's Corners by way of a cloverleaf interchange, the first of its kind in the vicinity of Utica.

At the time, the expressway began at what is now the Griffiss Air Force Base interchange east of Rome.

[15][16] In 1990, an interchange was constructed between Edic Road and the North–South Arterial (NY 5/8/12 and I-790) as part of a larger reconfiguration of the area surrounding New York State Thruway exit 31.

East of Edic Road, NY 49 utilized the pre-existing one-way highways paralleling the Thruway.

[citation needed] Ownership and maintenance of the remainder of River Road was transferred to the cities and towns it passed through.

[19] On October 11, 2002, a pedestrian bridge meant to connect a residential area to Whitesboro High School, under construction across the expressway in Marcy twisted and collapsed, killing one worker and injuring nine more.