On the afternoon of June 13, 1805, Lewis reached the first of the Great Falls of the Missouri River, a powerful waterfall in what is now Great Falls, Montana. He carefully measured and described each of the five main falls and many smaller cascades nearby. The first big fall he saw dropped about 80 to 90 feet, roaring so loudly that he could barely hear himself speak. Lewis did not get to enjoy the scene for long, because a grizzly bear soon appeared and chased him into the river, where he escaped by reaching an island and then climbing to safety.

The long way around all of the falls became one of the hardest jobs of the entire trip. To get past the Great Falls, the men had to make a portage, dragging their boats and supplies about 18 miles over rough ground filled with prickly pear cactus, clouds of mosquitoes and biting flies, and signs of rattlesnakes and grizzly bears. Wearing soft moccasins, they pulled heavy wagons with wheels cut from tree trunks and hauled six dugout canoes plus tons of baggage across the windy prairie. It took them close to a month and several trips back and forth along the portage route before every boat and every load was safely above the falls.