From near Grantsville, Maryland north to Ebensburg, Pennsylvania, U.S. Route 219 is Corridor N of the Appalachian Development Highway System. From Somerset, Pennsylvania to just south of Carrolltown, Pennsylvania, US 219 is a limited-access highway. From Carrolltown US 219 runs largely as a two-lane road to DuBois, Pennsylvania, through which it runs as Brady Street, and then returns to a two-lane road after a junction with Interstate 80. US 219 runs directly through the towns of Brockway, Ridgway, and Johnsonburg before reaching Wilcox, where PA Route 321 splits and heads for the town of Kane. US 219 continues north as a two-lane road until reaching Bradford, where it becomes a limited-access highway and remains so until reaching the New York border. On August 9, 2007, Pennsylvania State Transportation Secretary Allen D. Biehler unveiled four signs along US Route 219 that dedicated the route from Maryland to Cambria County, Pennsylvania as the Flight 93 Memorial Highway.

US 219 enters Pennsylvania from Maryland in Elk Lick Township, Somerset County, heading north as a two-lane undivided road through rural areas of farmland and woodland. The road intersects PA 669 in Salisbury before turning to the northeast. The route becomes a four-lane freeway and bypasses Meyersdale to the west, with US 219 Business serving the town. Past here, US 219 becomes a two-lane surface road again and winds through more rural areas, intersecting PA 653 in Garrett. The road heads northeast from here, turning to the northwest in Berlin. Southeast of Somerset, the route heads north onto a four-lane freeway. US 219 bypasses Somerset to the east and passes over the Pennsylvania Turnpike (I-70/I-76). The route interchanges with PA 281 before coming to a ramp with PA 601 that provides access to the Pennsylvania Turnpike. The road comes to the US 30 exit east of Jennerstown and heads through more areas of farms and woods, interchanging with PA 601 again followed by PA 403 northwest of Benson.

US 219 crosses the Stonycreek River into Cambria County and heads near suburban residential and commercial development southeast of Johnstown, coming to an interchange with PA 56. At this point, PA 56 forms a concurrency with US 219 and the road comes to an interchange with PA 756. PA 56 splits to the northwest onto a freeway at the next interchange and US 219 comes to an interchange with Galleria Drive, which provides access to The Johnstown Galleria shopping mall. The freeway heads into more rural areas of woods with some farms and reaches an interchange with PA 869 near the Johnstown Flood National Memorial. The next interchange along the US 219 freeway is with PA 53 in Summerhill. From this point, the road heads north through more rural areas, with a northbound exit and entrance at Tower Road. The route continues to the Ebensburg area, where it interchanges with US 22. From here, US 219 continues through wooded areas to the west of Ebensburg, coming to an interchange with the eastern terminus of the western segment of US 422. North of Ebensburg, the freeway segment of US 219 ends and the road heads north onto a two-lane undivided surface road, passing through more farmland and woodland. South of Carrolltown, the road intersects PA 553. After passing through Carrolltown, the route heads northwest, coming to an intersection with PA 271 in Northern Cambria. After this, US 219 begins to follow the West Branch Susquehanna River and curves to the north again, passes through forests and intersecting PA 240.

US 219 passes through Cherry Tree in Indiana County and intersects PA 580.

US 219 continues into Clearfield County and passes through more forested areas, running through Burnside and coming to an intersection with PA 286. The road continues northeast alongside the West Branch Susquehanna River and comes to a junction with PA 36, heading east concurrent with that route. In Mahaffey, US 219 splits to the northeast and passes through more wooded areas while following the river, intersecting with PA 969 and splitting from the river. In Grampian, the route reaches an intersection with PA 729 and PA 879, where it turns to the northwest. US 219 curves to the north again and continues through more woodland with some farms, curving to the northwest. The route comes to an intersection with US 322 in Luthersburg and forms a concurrency with that route, coming to a junction with PA 410 a short distance later. South of DuBois, US 322 splits from US 219 by heading to the west and US 219 continues northwest to an intersection with the northern terminus of US 119, turning north at this point. The route heads into developed areas of homes and businesses in DuBois, widening into a five-lane road with a center left-turn lane as it approaches the intersection with PA 255. Here, US 219 turns west onto a three-lane road with a center left-turn lane and passes through more developed areas of the city. The road leaves DuBois and heads through more rural areas with some development, widening into a four-lane divided highway and intersecting PA 830 before coming to an interchange with I-80.

US 219 heads north into Jefferson County and heads north through forests as a two-lane undivided road. The road heads into a mix of farmland and woodland, reaching Brockway. Here, the route intersects PA 28 and turns east, leaving the town and heading into more rural areas.

US 219 enters Elk County and continues northeast through more areas of woods and farms, intersecting PA 153. The road turns north and heads into more forested areas, coming to a junction with PA 948. At this point, PA 948 joins the route and the road heads northwest through more forests, descending a steep hill into Ridgway with US 219 Truck serving as a northbound truck bypass of the descent. In Ridgway, the road heads west and intersects PA 120 before US 219 splits from PA 948 by turning to the north. Past Ridgway, the route winds northeast through more forested areas alongside the Clarion River and reaches Johnsonburg, where it intersects PA 255 again. Past here, US 219 heads through more forested areas and comes to a junction with PA 321.

US 219 continues into McKean County and runs through more dense forests, intersecting US 6 west of Mount Jewett. Past this, the road winds north through the Allegheny National Forest and reaches a junction with PA 59. US 219 heads northeast through more of the national forest before leaving it and passing through Lewis Run. From here, the road continues north through more rural areas, forming a short concurrency with PA 770. The route reaches the Bradford area, where it heads into developed areas of homes and businesses and becomes a four-lane divided freeway. The road reaches its first interchange with Owens Way to the south of Bradford. The freeway continues into Bradford, bypassing the center of town to the east and interchanging with PA 346, at which point that route joins the freeway. The road turns northeast and interchanges with PA 46 before PA 346 splits to the east at the next interchange. The US 219 freeway continues north through rural areas, with the freeway ending at the New York border. At this point, US 219 continues north into New York.

U.S. Route 219 Business is a business route of U.S. Route 219 that travels for 4 miles through Meyersdale, Pennsylvania. The route was designated after a freeway bypass was constructed around the borough to avoid the variety of turns that the highway previously made through the municipality. The road travels as Beachley Street and Grant Street before becoming a rural road as it reconnects with its parent at the end of its freeway segment.

U.S. Route 219 Truck is a truck route of U.S. Route 219 that travels for 3 miles around Ridgway, Pennsylvania. The interesting route's main portion is one lane, functioning in the northbound direction only, to avoid the steep descent into the borough. Traffic is then funneled onto a portion of Pennsylvania Route 120 to connect back to the mainline.