Part of the highway runs through the Wichita Mountains Wildlife Refuge; this portion of SH-49 carries no signage identifying it as such.

Originally, it turned south in the refuge to serve Cache; its present-day routing was established in 1973.

SH-49 begins in Kiowa County at SH-54 south of Cooperton and heads due east.

The highway crosses into Comanche County about 2 miles (3.2 km) east of that point.

It serves as the northern terminus of Indiahoma Road, which heads south towards French Lake, the trailhead of the Dog Run Hollow hiking trail, and many of the peaks in the southwest part of the refuge, before eventually serving the town of Indiahoma south of the refuge.

At the Boulder Turnoff, it intersects the road leading to Lost Lake and Eagle Mountain.

Running south of Mount Cummins, it meets the southern terminus of State Highway 58.

The same year, the portion of road leading west from the Cache Wye to SH-54 was added to the highway, bringing it to its present-day extent.