The route begins in the Golden Triangle of Pittsburgh as a limited-access highway, following the bank of the Allegheny and Ohio rivers around the Manchester neighborhood, passing north of Acrisure Stadium and west of PNC Park.

Outside of the city, the road becomes a four-lane at-grade roadway to Rochester, with some portions featuring a divided highway.

Beyond US 19, PA 65 returns to at-grade level as a divided highway through the western sections of Pittsburgh.

At mile marker 2.9 near the Pittsburgh city line, PA 65 intersects the Blue Belt which crosses the Ohio River to the southwest on the McKees Rocks Bridge.

Leaving Sewickley, PA 65 crosses two more broughs (Edgeworth and Leetsdale) before exiting Allegheny County.

In Leetsdale, PA 65 meets the first terminus of the Red Belt at an intersection involving Cross Street.

When exiting Ambridge, PA 65 travels to the north paralleling the Ohio River as a divided road as it passes through Baden.

In 1973, a $16 million section opened to traffic with plans to continue the expressway to the Fort Duquesne Bridge.

In January 1988, Phase Two of the project began, which consisted of a new interchange between the expressway and the West End Bridge.

The bridge would be closed for two years while it underwent rehabilitation and new ramps were built at the northern end for the interchange.

The southern terminus was moved from Western Avenue to I-279 when the missing section in Ohio River Boulevard was finally completed in 1992.

In addition, a drive-in theater known as Spotlight 88 in North Sewickley Township retained its name after the route was redesignated, and is still known by that name as its current incarnation as a flea market after the drive-in was destroyed by an F3 tornado on May 31, 1985, as part of the 1985 United States-Canadian tornado outbreak.

It would end at a traffic circle on the North Shore of the Ohio River at the McKees Rocks Bridge.

The route that was built to relieve traffic and accidents on California Avenue was dedicated in August 1931 at a final cost of $12 million.

The missing gap which includes a connection to the West End Bridge did not open until January 1992.

From November 7, 1979, to March 1981, 15 people were killed on the boulevard, eight of those deaths occurring between the McKees Rocks Bridge and Manchester.

In February 2007, the route was extended northward from US 422 Business along East Washington Street to Croton Avenue.

The route was signed in September 2013 and followed the McKees Rocks Bridge over the Ohio River, PA 51, Neville Road, Grand Avenue, and I-79.