U.S. Highway 278 (US 278) runs west-east across the southern half of Arkansas for 258.8 miles (416.5 km).

As a result of its rural routing, US 278 has just one junction with an interstate highway, being I-30 at Hope.

In 1998, it was routed to its current western terminus in Wickes, replacing a vast majority of Arkansas Highway 4, which remains a distinct albeit short highway in southeastern Desha County.

US 278 is planned to be rerouted onto the proposed Charles W. Dean Bridge.

It is part of the plans to build Interstate 69 in Arkansas and in Mississippi.