It runs for 535 miles (861 km) from West Seneca, New York, at an interchange with Interstate 90 (I-90) to Rich Creek, Virginia, intersecting at US 460.

Until the early 1980s, US 219 continued southwest with US 460 from Rich Creek, re-entering West Virginia to end at US 19 in Bluefield.

US 219 continues through Greenbrier County running through the towns of Ronceverte, Lewisburg, where it intersects US 60, and Falling Spring.

After traveling through Accident it intersects Interstate 68 east of Friendsville, providing access to Morgantown, West Virginia, Frostburg and Cumberland.

From near Grantsville, Maryland north to Ebensburg, Pennsylvania, US 219 is Corridor N of the Appalachian Development Highway System.

US 219 runs directly through the towns of Brockway, Ridgway, and Johnsonburg before reaching Wilcox, where PA Route 321 splits and heads for the borough of Kane.

US 219 enters Western New York from Pennsylvania south of the Hamlet of Limestone in the Town of Carrollton in Cattaraugus County.

Separating from NY 417, the business route rejoins with the main US 219 and turns northward through the rest of Cattaraugus County, passing through Peth, Great Valley, Ellicottville, and Ashford Hollow before crossing the Cattaraugus Creek and entering Erie County.