The route heads from the Maryland border northwest through the southwestern corner of Chester County, intersecting US 1 in Nottingham.

PA 272 continues west into Lancaster County and intersects US 222 in Wakefield, where it turns north and passes through Buck before widening into a divided highway as it comes to another junction with US 222 in Willow Street.

North of Lancaster, US 222 splits at an interchange with US 30 and PA 272 becomes signed again, heading northeast parallel to the freeway alignment of US 222 and passing through Akron, Ephrata (where it intersects US 322), and Adamstown.

From the state line, the route heads north on two-lane undivided Chrome Road through a mix of farmland and woodland.

In the community of Chrome, PA 272 turns west on Christine Road and continues northwest through agricultural areas with some trees and homes.

Here, the route passes homes and comes to a bridge over an East Penn Railroad line before it intersects Baltimore Pike to the north of the Herr's Snacks plant.

PA 272 runs past a mix of residences and businesses and comes to a partial cloverleaf interchange with the US 1 freeway.

Past this interchange, the road heads through a mix of farmland and residential subdivisions, reaching the community of Glen Roy.

[2][3] PA 272 crosses the Octoraro Creek into Little Britain Township in Lancaster County and becomes Nottingham Road, curving northwest into agricultural areas with some trees and homes.

PA 272 enters Fulton Township and runs through agricultural areas with occasional homes, reaching an intersection with US 222 in the community of Wakefield.

At this point, the route turns north for a concurrency with US 222 along Robert Fulton Highway, running through a mix of farms and homes.

The route widens into a four-lane divided highway and the travel lanes split as the road heads northwest through wooded areas and passes under the Enola Low Grade Trail.

Both directions of PA 272 rejoin in the community of Smithville and it continues north as a four-lane divided highway through a mix of farms and woods with some homes and businesses, curving northwest.

PA 272 continues into West Lampeter Township and runs through more developed areas in Willow Street before it comes to a junction with US 222/PA 741.

Both directions of Willow Street Pike rejoin and it continues north as a two-lane undivided road past commercial development before it runs through wooded residential areas, passing through Hollinger.

The road briefly gains a center left-turn lane as it continues through wooded areas of development and passes to the west of a golf course.

[2][4] After crossing the Conestoga River, northbound US 222/PA 272 becomes Highland Avenue and southbound US 222/PA 272 is called South Prince Street.

The southbound direction intersects PA 324 in the community of Engleside before the two routes continue into the city of Lancaster, heading into urban residential and commercial areas.

The two routes continue northeast as a three-lane road with a center left-turn lane and runs past businesses and a few homes before it comes to an interchange with the US 30 freeway.

Here, US 222 heads east along US 30 and PA 272 continues northeast along Oregon Pike, passing through commercial areas and narrowing to two lanes.

The route heads through wooded areas and passes over Lititz Run before it comes to the eastern terminus of PA 722 near the community of Oregon.

Past this, PA 272 narrows back into a two-lane undivided road and runs through a mix of farm fields and commercial development, curving to the north.

[2][4] The route fully enters Ephrata Township and narrows to a two-lane road as it runs through a mix of farmland and commercial development, passing over an East Penn Railroad line.

The route curves northeast past commercial development and comes to an intersection with Colonel Howard Boulevard, which heads east to provide access to the US 222 freeway and the Pennsylvania Turnpike (Interstate 76) at the Reading interchange.

[2][4] PA 272 enters Brecknock Township in Berks County and passes commercial development before it comes to its northern terminus at a partial cloverleaf interchange with the US 222 freeway.

[18] In 2006, the intersection with US 222 and PA 568 at the northern terminus was replaced with an interchange as part of upgrading US 222 to a freeway between Adamstown and Reading.