The expedition was now divided into two groups; while the group led by Lewis would search for the source of the Marias River, Clark's group looked for a way to cross the Rocky Mountains on the way back east, wanting to avoid a delay like the one they had experienced while crossing the Bitterroot Mountains. Sacajawea traveled with Clark and was able to show the group the Shoshoni route through the peaks, now called the Bozeman Pass. Before reaching the pass, this route took the group through a great deal of swampy terrain. Clark was pleased with Sacajawea's guidance, but some of his subordinates complained that she was taking them on an unnecessarily long and difficult route. Despite the difficulties, Sacajawea's leadership got Clark's group to the Yellowstone River by July 15.

Meanwhile, Lewis and his team were searching for the river source. During this exploratory mission, Lewis and his men encountered a group of Blackfeet Indians. Without Sacajawea and little Jean Baptiste ("Pomp") along, Lewis had little way to convince the Blackfeet group that they were not a raiding party. The result was a minor conflict in which two Blackfeet were possibly killed. Thus the only expedition's only serious skirmish with Native Americans took place due to Sacajawea's absence.

At the same time that Lewis was exploring the Marias area and skirmishing with Indians, Sacajawea and the rest of Clark's party were riding the rapidly flowing Yellowstone River. Reaching the mouth of the river, Clark's party encountered incredibly thick concentrations of mosquitoes. Infant Jean Baptiste was bitten so badly that Clark moved the expedition to a different spot to wait for Lewis, a major demonstration of Clark's concern for Sacajawea's son. Although Lewis and his men had planned to meet Clark's group at the first spot, Clark simply left a message on a piece of paper tied to a pole giving directions to the new camp.

Now that Sacajawea was leading Clark's team as it approached the Rocky Mountains, she was increasingly becoming the main guide of the expedition, or at least of Clark's group. Since she had already proved her reliability so many times, Clark had no qualms about trusting her to steer them now. Because the Bozeman Pass was preceded by swampy terrain, some commentators have suggested that Sacajawea made a bad decision and put the expedition in an uncomfortable situation, perhaps even endangering the mission. However, Sacajawea can hardly be blamed: she merely was showing them the path the Shoshoni themselves traditionally preferred. Sacajawea first interested Clark in taking this path by telling him they stood a good chance of encountering a large herd of buffalo if they took this route. Always looking for food sources, Clark delighted in this prospect, and indeed, the group soon came across some buffalo. These provided a useful supply of food, though Charbonneau fell off his horse while chasing one and badly injured himself. Although some historians have condemned Sacajawea's leadership as a guide, Clark himself was always pleased with her, noting repeatedly in her journal how "remarkable" she was. From Clark's perspective, Sacajawea was saving the expedition a lot of time and trouble.

Lewis, traveling separately from Clark and Sacajawea, consistently ran into more problems. (This was due partially to Sacajawea's absence, partially to Lewis's own foolhardiness.) Without Sacajawea and her baby letting the Blackfeet know that this was no war party, Lewis made a mostly vain attempt at peace and diplomacy by giving the Blackfeet Jefferson medals. While they were camped, the Blackfeet stole most of the Lewis group's rifles. In the ensuing scuffle, one of the Blackfeet group was stabbed, and Lewis pulled out his pistol and shot another in the stomach. Lewis and his men jumped on their horses and galloped sixty exhausting miles to get away. Both sides were frightened by the incident. Not knowing that the white men were fleeing, the Blackfeet jumped on their horses as well, and fled in the opposite direction.

On the trip down the Yellowstone, Sacajawea and Clark's group passed a large rock in the river. The group stopped and Clark carved his name into the rock, where it is still visible today. Buffalo and grizzlies abounded in this area, and the presence of these animals often slowed Clark's team. More cautious than Lewis, however, Clark managed to get his men through these dangers fairly safely. Meanwhile, as Lewis tried to make it to the rendezvous point, one of his own men accidentally shot him, thinking he was an elk. While Lewis's men were so hungry they mistook their own captain for a food source, Sacajawea always kept Clark's group well fed, now finding wild gooseberries in the Yellowstone region.