The road runs through wooded areas and passes over the Christina River before it comes to a bridge over Amtrak's Northeast Corridor railroad line.

The roadway curves east and widens into a four-lane divided highway as it passes to the south of the University of Delaware's Science, Technology, and Advanced Research campus.

The route continues to the community of Ogletown and passes to the southeast of the Delaware School for the Deaf before it has an intersection with Salem Church Road and an interchange with DE 273.

Beyond the hospital, DE 4 comes to an intersection with the western terminus of DE 58 and Delaware Park Boulevard, the latter of which is an access road to Delaware Park – which consists of a Thoroughbred horse racetrack, casino, and golf course – and the Churchmans Crossing station on SEPTA's Wilmington/Newark Line that runs along the Northeast Corridor.

[3][4] At this point, DE 4 turns north for a concurrency with DE 7 on the six-lane divided Stanton Christiana Road, running through wooded areas with nearby development, including the Hale-Byrnes House, and passing over Amtrak's Northeast Corridor railroad line and the White Clay Creek and Mill Creek near their confluence.

At this point, the two routes head into a commercial area and split into the one-way pair of Mitch Road eastbound and Main Street westbound.

DE 4 continues east along the one-way pair past homes and businesses with two lanes in each direction, crossing Red Clay Creek.

Past this, the route heads across Little Mill Creek and passes north of a park and ride lot before crossing CSX's Market Street Industrial Track railroad line at-grade.

Past this, DE 4 enters downtown Wilmington and splits into the one-way pair of Maryland Avenue eastbound and South Monroe Street westbound before ending at DE 48, which is routed on the one-way pair of Martin Luther King Jr. Boulevard eastbound and West Second Street westbound.

[3][4] The section of DE 4 between Harmony Road near Christiana and Jackson Street in Wilmington is part of the Washington–Rochambeau Revolutionary Route, a National Historic Trail.

[6] What would become DE 4 east of Christiana was part of a King's Highway constructed in the 17th century connecting Philadelphia to points south.

[23][24] The concurrent DE 2 designation was removed from the Christiana Parkway in 2013 as part of simplifying the route numbers in Newark.