U.S. Route 6 travels east–west near the north edge of the U.S. state of Pennsylvania from the Ohio state line near Pymatuning Reservoir east to the Mid-Delaware Bridge over the Delaware River into Port Jervis, New York. It is the longest highway segment in the Commonwealth. Most of it is a two-lane rural highway, with some freeway bypasses around larger towns. Except east of Scranton, where it is paralleled by Interstate 84, it is the main route in its corridor. What is now Interstate 80—the Keystone Shortway—was once planned along the US 6 corridor as a western extension of I-84. The corridor was originally the Roosevelt Highway from Erie, Pennsylvania to Port Jervis, New York, designated Pennsylvania Route 7 in 1924. The PA 7 designation soon disappeared, but as US 6 was extended and relocated, the Roosevelt Highway followed it. The Pennsylvania section of US 6 was renamed the Grand Army of the Republic Highway in 1946; this name was applied to its full transcontinental length by 1953.

US 6 meets with U.S. Route 19 near Meadville, where it turns north with US 19 to a point east of Edinboro. There it turns east (while U.S. Route 6N heads west to U.S. Route 20 at West Springfield) and passes through the Northern Tier of Pennsylvania. At Towanda it turns more southeasterly to reach Scranton, then turning back northeast out of Scranton to Carbondale and generally east and southeast to New York. US 6 fully encompasses two Pennsylvania Scenic Byways: the Gateway to the Endless Mountains Scenic Byway along the bypass of Tunkhannock and the Governor Casey Scenic Byway along the freeway portion in Lackawanna County between I-81 in Dunmore and PA 247 in Jessup.

As approved by the American Association of State Highway Officials (AASHO) on November 11, 1926, the west end of US 6 was at Kane, where U.S. Route 120 continued west to Erie. (US 6 ended concurrent with U.S. Route 219, which ran east to Mt. Jewett along US 6 before turning north to New York.) US 6 also used present Pennsylvania Route 706, U.S. Route 11 and Pennsylvania Route 106 between Wyalusing and Carbondale, while U.S. Route 106 took the southerly route via Scranton.

By the end of 1927, US 6 had replaced US 120 in running west from Kane to Erie (making US 120 no longer connect to its "parent" U.S. Route 20), and had swapped places with US 106 via Scranton; this took it along the Jefferson Highway. It was defined by AASHO to serve the following places in Pennsylvania: Erie, Waterford, Corry, Warren, Kane, Farmers Valley, Coudersport, Wellsboro, Canoe Camp, Mansfield, Towanda, Wyalusing, Tunkhannock, Clarks Summit, Scranton, Carbondale, Honesdale, Milford, and Matamoras. By 1930 its west end was at 26th Street (U.S. Route 20) and State Street (US 6 - now Pennsylvania Route 505) in Erie. (By then U.S. Route 19 ended a block to the west on Peach Street, where it still ends today.)

This original routing deviates majorly from present US 6 in the following places, roughly using the following current routes:

In 1931, US 6 was extended west to Greeley, Colorado. It left its old route - which then became U.S. Route 6N - at Waterford, and headed south on former Pennsylvania Route 5 and U.S. Route 19 and west on U.S. Route 322 and former Pennsylvania Route 77 into Ohio. This whole section from Waterford to Cleveland, Ohio was regarded as temporary, but the only change was a relocation by 1936 along Pennsylvania Route 79 from Union City west to US 19 south of Waterford. (Former US 6 from Mount Union to Waterford became Pennsylvania Route 97. At the same time, US 6N was moved to the rest of former PA 79 from US 19 west to U.S. Route 20 - its current route.)

Since then, only minor realignments and bypasses have been made to the route of US 6.