The state highway runs 35.39 miles (56.95 km) from Camp Peary near Williamsburg east to U.S. Route 258 (US 258) at Fort Monroe in Hampton.

SR 143 is a major local thoroughfare on the Virginia Peninsula portion of the Hampton Roads metropolitan area.

The state highway crosses Queen Creek into the city of Williamsburg and meets the northern end of SR 5 (Capitol Landing Road).

The state highway heads southeast and enters James City County at its intersection with SR 641 (Penniman Road).

The two highways have mirror-image partial cloverleaf interchanges with SR 199 (Humelsine Parkway) as they re-enter York County.

[1][2] SR 143 continues east into James City County as a four-lane undivided highway that closely parallels I-64 to the north and the railroad to the south while passing through a forested area.

Southeast of the airport, SR 143 crosses to the south side of I-64 at a cloverleaf interchange adjacent to Patrick Henry Mall.

SR 143 enters Hampton for good at Pear Avenue, where the highway continues as Victoria Boulevard.

The two highways meet the southern end of SR 134 (Armistead Avenue) and head as a two-lane divided street through downtown Hampton, which contains St. John's Episcopal Church and the Virginia Air and Space Center.