The entire course of the river is located within the boundaries of Yellowstone National Park in Wyoming, US.

The river reemerges at the southern end of Lewis Lake and flows in a general southerly direction through a steep canyon roughly paralleling the south entrance road toward the south entrance of the park.

The Snake soon flows out of Yellowstone into Grand Teton National Park and Jackson Lake.

The Lewis River has rapids up to Class VI and takes a 29-foot (8.8 m) drop at Lewis Falls, the most famous of many waterfalls and rapids on this short but scenic river.

Brown, rainbow and Yellowstone cutthroat trout are found in the river.