It goes due north from here, passing through a remote part of Fort Sill before reaching the Wichita Mountains Wildlife Refuge.

For the remainder of its time in Comanche County, the highway follows an irregular northwest heading as it passes through the Wichita Mountains.

The highway bridges Spring Creek, a tributary of the Washita River, then curves to the northeast.

After turning back to the north, the road passes through Cowden, where it crosses Gyp Creek.

At this time, SH-49 began at US-62 in Cache proper (US-62 had not yet been shifted to the freeway north of town), entered the Wichita Mountains National Wildlife Refuge, then emerged near Medicine Park and followed the remainder of SH-49's present day routing.

As originally added to the system, only the portion of highway between the northern SH-19 junction and the Washita River bridge was paved.

[1] The section of SH-49 connecting to Cache to the refuge was renumbered to be part of SH-115 in 1962, giving the highway the same basic routing that it has today.

[6] In 1964, the portion of gravel roadway through the Wichita Mountains between Meers and the Comanche–Kiowa County line was removed from SH-115.