PA 53 begins at an interchange with the US 219 freeway in Croyle Township, Cambria County, heading east-northeast on four-lane divided Railroad Street.

The route heads into wooded areas again and crosses under the Pittsburgh Line, turning northeast to fully enter Wilmore and pass near residences.

[2][3] PA 53 heads into residential areas as a two-lane undivided road and crosses into the borough of Cresson at the Admiral Peary Highway intersection.

The route winds north-northeast through more rural areas with occasional homes a short distance to the west of the railroad tracks, running through Amsbry.

The route crosses into Reade Township and becomes Glendale Valley Boulevard, running through more forests with sparse fields and residences and turning northwest through Frugality before heading north again.

The road intersects the northern terminus of PA 865, where it crosses into the borough of Coalport and becomes Main Street, passing homes and businesses.

The route heads back into Beccaria Township and continues into the community of Blain City, turning east and north along Dorsey Avenue.

The route reenters Beccaria Township and becomes Glen Hope Boulevard, heading into forested areas with some homes and turning north.

The route heads back into rural areas and crosses into Bigler Township, becoming Main Street and continuing to the northwest of Clearfield Creek.

In Coal Run Junction, PA 53 becomes Sarah Street and heads east through rural areas of commercial development to the north of a R.J. Corman Railroad line before crossing into the borough of Osceola Mills.

The road turns northeast and heads back into Decatur Township, becoming Walton Street and passing through wooded areas with some fields and homes.

The road heads into business areas and gains a center-left turn lane, becoming the border between Phillipsburg to the west and Rush Township to the east.

[2][5] The road crosses the Moshannon Creek back into Decatur Township in Clearfield County, where PA 53 splits from US 322 by heading north-northeast on two-lane Troy Hawk Run Highway.

The road turns north again and comes to the residential community of Morrisdale, where it curves northeast into a mix of farmland and woodland with some homes.