The state took over the road in 1917 and it became a part of the Buchanan Highway, which ran between Mount Union and the Maryland border in Carroll Valley.

PA 16 begins at an intersection with US 522 in the center of the borough of McConnellsburg in Fulton County, heading east-southeast on two-lane undivided Lincoln Way.

The route splits from Lincoln Way by turning southeast onto Buchanan Trail and enters Ayr Township, running past businesses before heading near homes and passing to the northeast of an industrial building.

The route continues east and enters the borough of Greencastle, where it becomes West Baltimore Street and passes a few homes before it comes to an intersection with US 11 in a business area.

Past this intersection, PA 16 crosses under Norfolk Southern's Lurgan Branch railroad line and heads into the downtown area of Greencastle, coming to a traffic circle at Carlisle Street.

The route runs east-southeast through more rural land and passes under CSX's Lurgan Subdivision railroad line before it heads to the south of the community of Waynecastle, at which point it enters Washington Township.

The road passes near farm fields before it enters the borough of Waynesboro and becomes West Main Street, where it is lined with homes.

The route fully enters Washington Township and curves east-southeast, passing businesses with nearby residential areas in the community of Wayne Heights as a three-lane road with a center left-turn lane.

[3][5] The road leaves the Cumberland Valley and heads into forested areas in the South Mountain range, curving northeast and gaining a second eastbound lane.

The route continues to ascend the mountain and gains a center left-turn lane before turning to the east, passing near the community of Beartown.

The route runs past a few businesses and curves to the east, crossing CSX's Hanover Subdivision railroad line at-grade to the north of Blue Ridge Summit.

The route runs through more wooded areas with some development and passes through the community of Fountain Dale, heading north of the Raven Rock Mountain Complex.

PA 16 crosses back into Liberty Township and continues through forested areas with residential development as it skirts the southern border of the borough of Carroll Valley in three locations.

PA 16 reaches its eastern terminus at the Maryland border, where the road continues southeast into that state as MD 140.

[9] In 1913, the section of current PA 16 in McConnellsburg became part of the Lincoln Highway, an auto trail that ran from San Francisco to New York City.

[21][22] In 1967, US 30 was rerouted along a bypass north of McConnellsburg, allowing PA 16 to be extended westward along Lincoln Way to its present terminus at US 522.