PA 72 was designated in 1927 to run concurrent with US 230 between the Maryland state line and Lancaster, with US 222 replacing US 230 a year later.

The southern terminus was cut back to Lancaster in the 1960s, with PA 272 replacing the route between Wakefield and Willow Street.

The route passes to the west of the Lancaster County Convention Center before it intersects King Street, which carries eastbound PA 462, at Penn Square, where the Soldiers and Sailors Monument is located.

At this point, the northbound direction of PA 72 turns west to run concurrent with southbound US 222/PA 272 on McGovern Avenue, forming the border between Manheim Township to the south and a part of the city of Lancaster to the north.

The road curves northwest and continues back into the city of Lancaster, where it heads past businesses and industrial establishments.

PA 72 crosses back into Manheim Township and widens to a four-lane undivided road as it comes to a partial interchange with the US 30 freeway, with access to westbound US 30 and from eastbound US 30.

PA 72 intersects Plaza Boulevard, an entrance road to the Park City Center shopping mall to the southwest.

The road passes to the east of an industrial complex before it reaches a partial cloverleaf interchange with the PA 283 freeway.

The road curves northwest and narrows to two lanes as it fully enters East Petersburg and runs through residential areas, coming to an intersection with PA 722 in the center of the borough.

The road heads through agricultural areas with occasional residential and commercial development and curves north to cross into Penn Township.

PA 72 continues through rural areas and passes to the east of the large Manheim Auto Auction facility.

The road continues past homes and businesses and crosses Chiques Creek into the borough of Manheim, where it runs through commercial areas on South Main Street and intersects PA 772.

The route curves north and leaves Manheim for Rapho Township, where it becomes Lebanon Road and heads through a mix of farmland, trees, and homes, turning northwest.

The road curves north and crosses Chiques Creek into Penn Township, where it reaches the community of Elstonville and turns west.

PA 72 heads across the creek back into Rapho Township and winds northwest through a mix of farmland and woodland with a few homes.

Past this, the freeway crosses into West Cornwall Township and PA 72 splits from US 322 at a partial interchange, heading north onto two-lane undivided Quentin Road into the Lebanon Valley.

The route passes fields before coming to an intersection with PA 419 in a commercial area east of the community of Quentin.

The route heads into residential areas with some commercial development and enters the city of Lebanon, where the roadway becomes city-maintained.

North of here, the route crosses the Quittapahilla Creek and heads into industrial areas, where both directions come to bridges over Norfolk Southern's Harrisburg Line and Scull Street.

At this point, both directions of PA 72 head west along Maple Street, a two-way, two-lane undivided road that runs through commercial areas before entering woods.

PA 72 continues through areas of farms and woods with some homes and businesses as an unnamed road, entering Swatara Township and bending northwest to pass through the residential community of Bunker Hill.

Farther north, the road reaches the community of Lickdale, where it passes businesses and homes and intersects Fisher Avenue, which heads west to a partial cloverleaf interchange with I-81 and Fort Indiantown Gap.