Known for most of its length as Pembroke Avenue, the state highway runs 8.81 miles (14.18 km) from U.S. Route 60 (US 60) in Newport News east to Second Street in Hampton.

SR 351 begins at eastbound US 60 (Huntington Avenue) within parking lots serving the waterfront industrial area to the west and near The Apprentice School in the East End of the independent city of Newport News.

East of the ramps, SR 351 expands to a four-lane undivided street and has a long, oblique underpass of Interstate 664 (I-664) (Hampton Roads Beltway).

SR 351 heads east between I-664 immediately to the north and the Hampton Branch rail line one block to the south.

SR 351 follows a three-lane road with a center left-turn lane to its junction with US 258 (Mercury Boulevard), then veers northeast as a four-lane undivided highway toward the Buckroe Beach neighborhood of Hampton.

The two highways run concurrently east to Mallory Street, onto which SR 169 turns south toward the Phoebus neighborhood of Hampton.