U.S. Route 65 (US 65) runs north–south through southeastern and north central Arkansas for 309.52 miles (498.12 km).

US 65 enters the state from Louisiana south of Eudora, running concurrently with the Great River Road.

US 65 runs through the major cities of Pine Bluff and Little Rock.

US 65 is largely a four-lane divided highway, except for its overlaps with Interstates, two-lane section between Louisiana and Lake Village, and many undivided highway sections north of I-40.

While the majority of the route travels through rural portions of Arkansas far from any Interstate Highways, the route does have a 79.52-mile (127.98 km) concurrency with I-530, I-30, and I-40 between Pine Bluff and Conway through the Little Rock metropolitan area.

US 65 enters Arkansas from Louisiana and follows the Great River Road.

The original US 65 between Pine Bluff and Conway is now signed Arkansas Highway 365.