It runs south through Conway beginning as Skyline Drive to intersect Old Morrilton Highway (US 64).

Continuing south, US 65B passes the Joclin-Bradley-Bowling House and the Patterson, Walter, Filling Station, which are both listed on the National Register of Historic Places.

US 65B also passes within a block of the Van Buren County Courthouse, south of which the route terminates at US 65/AR 9.

Just west of Main Street's intersection with Central Avenue is the Boone County Jail, where Henry Starr died of wounds inflicted by a rifle while attempting to rob a Harrison bank.

South of Crooked Creek, the route winds east to serve the fairgrounds and North Arkansas College before terminating at US 62/US 65/US 412.

Next to the overpass lies the original southern terminus; removed when US 65 was upgraded to a 4-lane Expressway south of Lake Taneycomo.

Shortly after the Turkey Creek bridge, Business 65 is the western terminus of Missouri BB, which runs east toward the Hollister High School.

Signage in Branson then takes Business 65, concurrent with Missouri 76, through downtown, then heads west by turning left at Main Street.

Business 65 originally continued straight onto Veterans Boulevard, instead of turning onto Main Street.

Also, a Business 65 bannered shield is attached to the side of the Roark Creek bridge just north of downtown; however, the sign cannot be seen from the roadway itself.

Business 65/Route 14 then turn West onto Jackson Street, promptly crossing over the Finley River Bridge.

The highways continue west for about 1 mile to an interchange at US 65; along the way, Business 65/Route 14 is the southern terminus for Missouri Route NN/9th street, which runs north to the Ozark High School.

U.S. Route 65 Business in Springfield parallels US 65, which follows the Schoolcraft Freeway along the east edge of town, for its entire length.

U.S. Highway 65 Business starts at the junctions of Missouri Route 6 and US 65 and runs west a few hundred yards before turning north onto Oklahoma Avenue.

The route followed the Airline Highway around what was then the outside of town, allowing through traffic from the south and east to access the Mississippi River Bridge while avoiding the downtown area.