The route passes northeast of the Caravel Academy before it turns north and comes to an intersection with US 40 in a commercial area to the east of Glasgow.

At this intersection, the route name changes to South Chapel Street and it passes through fields with some development, crossing under Interstate 95 (Delaware Turnpike) without an interchange.

[3][4] Following this intersection, the road narrows to two lanes as it heads through agricultural areas to the east of the University of Delaware campus.

The road bends north into commercial areas, passing to the east of Newark High School and widening into a four-lane divided highway as it comes to an intersection with Delaware Avenue, which carries the eastbound direction of DE 273.

The road leaves Newark and heads northeast through residential areas, briefly becoming undivided as it crosses White Clay Creek.

In Milford Crossroads, the route turns northeast onto Paper Mill Road and curves north to pass between White Clay Creek State Park to the west and the Middle Run Valley Natural Area to the east, crossing Middle Run a third time.

[9][10] The portion of the road between US 13 and US 40 was improved by the state in 1937, providing a better route to Baltimore and Washington, D.C. for residents in the Delaware City, Port Penn, and Odessa areas.

[13] The concrete bridge carrying Paper Mill Road over the White Clay Creek was completed in 1947, with final work on the project finished in August 1949.

[18] In 1980, the Chapel Street grade crossing of the Northeast Corridor rail line in Newark was removed, and DE 72 was realigned farther to the east to follow Library Avenue across the railroad tracks before continuing north on DE 2 and Possum Park Road to Paper Mill Road in Milford Crossroads.