State Highway 101 begins at US-59 approximately 3 miles (4.8 km) north of Sallisaw. From this terminus, SH-101 travels due east, crossing over Little Sallisaw Creek shortly before passing through the unincorporated place of Akins. Two miles (3.2 km) east of Akins, the road makes a sharp turn northward. During this 1-mile (1.6 km)-long stretch of north–south roadway, the road passes Sequoyah's Cabin. The road gradually curves back to the east as it crosses Big Skin Bayou. Upon encountering Black Creek, a tributary of the bayou, the road makes an abrupt turn back to the north.
Another gradual curve returns SH-101 to an east–west alignment which persists until the junction with State Highway 64B near Eagle Mountain. This is the northern terminus of the highway, which heads south to Muldrow and eventually to Interstate 40. SH-101 continues north from this point, curving around the mountain and proceeding along a very winding route. During this section, the road crosses Polecat Creek and Little Lee Creek. After a short southeast section, SH-101 turns to a due east alignment, crossing Big Lee Creek on a narrow through truss bridge and passing just north of the unincorporated CDP of Short. The highway then gradually stairsteps northeast, culminating in a brief north–south section along the Oklahoma–Arkansas state line. The roadbed then curves east, entering Arkansas and the Ozark National Forest, and becoming Highway 220 toward Uniontown.