PA 54 begins at an intersection with US 15 in Clinton Township, Lycoming County, heading east on a two-lane undivided road.

[2][3] The road crosses the West Branch Susquehanna River and leaves Montgomery for Muncy Creek Township, becoming unnamed and turning southwest into wooded areas.

[2][4] PA 44/PA 54 head into Limestone Township in Montour County and the road becomes Continental Boulevard, passing through more rural areas.

[2][4] PA 54 crosses the Chillisquaque Creek before it enters the small borough of Washingtonville, where the name becomes Water Street and the route is lined with homes along with a few businesses.

The road heads back into Derry Township and becomes Continental Boulevard again, running through woods before coming to a junction with PA 254.

PA 54 crosses into Mahoning Township and heads through a gap in forested Montour Ridge, passing near some development.

Immediately after the railroad crossing, the route turns southeast onto Elysburg Road and runs between residential areas to the southwest and the Sunbury Line and the Susquehanna River to the northeast.

The road leaves Riverside for Rush Township and heads through wooded areas alongside the railroad tracks and the river.

[2][4] The Sunbury Line and Susquehanna River curve east away from the road and the route continues southeast through farmland with some woods and development.

The route curves south and becomes North Market Street, heading through farmland with some development and narrowing back to two lanes.

The road turns west and then south, becoming Locust Gap Highway and crossing the Shamokin Valley Railroad before coming to an intersection with PA 901.

[2][4] PA 54 enters Conyngham Township in Columbia County, crossing the Reading Blue Mountain and Northern Railroad line before passing through Locustdale as Main Street.

The route leaves Ashland for Butler Township again and heads into forested areas, turning northeast and crossing the Mahanoy Creek before passing through Big Mine Run.

[2][6] PA 54 enters the borough of Girardville as West Mahanoy Avenue and runs between woods to the north and residential areas to the south.

[2][6] Here, the road becomes West Centre Street and runs between Shenandoah Valley Junior Senior High School to the north and businesses to the south before becoming lined with homes.

In Saint Nicholas, PA 54 turns east onto West Centre Street and heads past more coal mines as it runs north of a Reading Blue Mountain and Northern Railroad line.

[2][6] The route heads into the borough of Mahanoy City as West Centre Street and turns east, passing businesses before running through residential areas.

PA 54 curves east and heads near some development, passing under a Reading Blue Mountain and Northern Railroad line before reaching a modified cloverleaf interchange with I-81.

[2][6] Following this interchange, the route narrows to a two-lane undivided road and heads northeast through forests, crossing into Ryan Township and becoming Barnesville Drive.

PA 54 heads east near more developed areas and passes through Park Crest, crossing the Reading Blue Mountain and Northern Railroad's Reading Division line and turning south-southeast to parallel the railroad tracks through wooded areas with some fields and development.

The route runs east-northeast through wooded areas with some farm fields and residences as it follows Pine Creek and the Reading Blue Mountain and Northern Railroad tracks, passing through Barnesville.

PA 54 runs past more homes before it leaves Hometown, turning southeast as it passes through a mix of fields and development.