The river flows through the valley for more than sixty miles before it turns eastward where it enters a canyon. The Big Hole River picks up further velocity through this stretch and riffles become more frequent. A few small rapids also exist. The canyon is initially heavily forested on both sides of the river, but the forest lessens as the river travels further eastward and loses additional elevation. Access to the river in the canyon stretch is excellent. The Big Hole River is frequently bordered by federal land, and numerous official and unofficial access sites exist.

The canyon stretch of the Big Hole River continues for thirty miles, passing through the very small town of Wise River. The Big Hole then emerges from the canyon near the town of Divide, which is located along Interstate 15.

From Divide, the river turns south and flows through primarily arid country, with cottonwood trees frequently lining its banks, to the town of Glen. The best access to the Big Hole River in this stretch is from the designated access sites, as the river primarily flows through private land.

After twenty-five miles, the river makes one final turn and begins to flow to the northeast, through very arid terrain, towards the confluence with the Jefferson River at Twin Bridges. There are only four designated access sites between Glen and Twin Bridges. However, a number of unofficial access sites exist just off the road that follows the Big Hole River.