Commissioned in 1927 by the Pennsylvania Department of Highways, PA 44 originally ran from the New York state line to Jersey Shore.

[4][5] The route enters Anthony Township in Montour County, passing homes in the community of White Hall and running through agricultural and wooded areas in the Muncy Hills, turning to the west.

The road runs through a patch of woodland before it crosses into the borough of Turbotville, where it gains a center left-turn lane and passes businesses.

[7] PA 44 enters Washington Township in Lycoming County and continues west through agricultural areas in the White Deer Valley.

The route comes to an intersection with the southern terminus of PA 654 and heads west through agricultural areas, passing homes in the community of Oval.

The route and the creek head north through a gap in the forested Bald Eagle Mountain range, crossing into Nippenose Township.

North of the gap, PA 44 runs near homes as it passes to the west of the community of Antes Fort and comes to a bridge over Norfolk Southern's Buffalo Line.

At this point, PA 44 forms a wrong-way concurrency with US 220 on a four-lane freeway officially signed as the "Frank D. Oreilly Highway", heading west into Porter Township.

The freeway heads through wooded areas to the north of Jersey Shore, coming to a bridge over the Lycoming Valley Railroad.

The road enters the Tiadaghton State Forest and crosses into Cummings Township, turning west to pass through the community of Ramsey.

The road continues northwest into McHenry Township and reaches a junction with the northern terminus of PA 664 in the community of Haneyville.

The road bends back to the north and runs along the boundary of Grugan Township, Clinton County, to the west and McHenry Township, Lycoming County, to the east as it runs between the Sproul State Forest to the west and the Tiadaghton State Forest to the east.

[4][8][9] The route fully enters Brown Township in Lycoming County and continues north through the Tiadaghton State Forest as an unnamed road, passing through the community of Pump Station.

The road heads back into the Susquehannock State Forest and traverses Mount Brodhead, crossing into West Branch Township.

The route runs to the west of Mill Creek and heads north through wooded areas with some farm fields and residences.

PA 44 heads into Sweden Township and continues through a mix of fields and woods with some homes and commercial development, crossing the creek.

The two routes head northwest through wooded areas with some fields and residential and commercial development to the north of Mill Creek, crossing into Eulalia Township.

US 6/PA 44 becomes East 2nd Street and reaches an intersection with the northern terminus of PA 872, continuing west through forests and development.

US 6/PA 44 crosses the Allegheny River and heads into the downtown area of Coudersport, passing to the south of the Potter County Courthouse.

The route continues between forests to the west and residential areas and the Allegheny River to the east before it leaves Coudersport for Eulalia Township, becoming an unnamed road.

The route turns northwest and passes through the community of Hebron Center, continuing through wooded areas with some farm fields and residences.

The route crosses the Oswayo Creek and heads through the community of Millport as it runs through more fields and woods with some development, passing through Sharon Center.

PA 44 continues northwest and enters the borough of Shinglehouse, where the name becomes South Stevens Street and it runs through residential areas with some businesses, passing to the northeast of Oswayo Valley High School.

The route curves north before it turns west onto Academy Street, heading past homes before passing businesses in the center of Shinglehouse and bending southwest.

Farther northwest, PA 44 reaches the community of Ceres and crosses the Oswayo Creek before coming to its northern terminus at the New York border.