The one-way pair, which carries two lanes in each direction, passes through suburban residential areas.

DE 100 curves north and enters the town of Elsmere, where it runs through industrial areas and comes to a bridge over Little Mill Creek, B&O Lane, CSX's Philadelphia Subdivision railroad line, and Baltimore Avenue.

The road continues through residential and commercial areas, crossing Chestnut Run and widening into a divided highway as it comes to an intersection with DE 141.

The roadway curves northeast and passes under the East Penn Railroad before coming to a partial cloverleaf interchange with DE 52 in Greenville.

[3][4] DE 100 continues north through wooded areas with fields and homes, crossing the East Penn Railroad line again at-grade.

The road runs through Montchanin and passes to the east of the Wilmington Country Club before crossing the railroad tracks again at-grade and coming to an employee entrance to the Winterthur Museum and Country Estate to the west.

[11] By 1932, the state highway had been completed from Elsmere north to the Kennett Pike intersection while the remainder was still a county route.

[15] In 2003, the southern terminus of PA 100 was moved from the Delaware border to U.S. Route 202 north of West Chester.

Emergency repairs took place and the bridge was expected to be reopened by the end of March.