Before the Lewis and Clark Expedition moved on, Cameahwait described the route the explorers should take to the Columbia River, which would lead them to their goal, the Pacific Ocean. On August 24, 1805, Clark decided to follow this land route. Meanwhile, the Shoshoni were preparing to move their camp in pursuit of buffalo herds. At this point, Clark (with Sacajawea's aid) begged for more horses, and Cameahwait ultimately provided the expedition with 29 horses by August 29. Cameahwait even took the trouble to send a guide along with the expedition, a Shoshoni called Toby.

The route to the Pacific involved crossing the Rocky Mountains, so the expedition had to portage their boats once again. The many Shoshoni horses Sacajawea had negotiated for proved tremendously valuable in moving the boats a long distance over land. The expedition made good time until early snows in September slowed them down. While crossing the Bitterroot Mountains, the path became especially treacherous and the expedition lost several of its horses. One horse fell and crushed Clark's writing desk, depriving him of a good place to work on his journal entries. After hauling the heavy desk for so many miles, the expedition now used it for firewood.

On September 20, 1805, the expedition made it out of the Bitterroot Mountains and into the area inhabited by the Nez Perce (The Nez Perce had been given that name by the French because of their habit of piercing their noses and wearing shells, beads or jewelry in them.) Lewis and Clark got along well with the Nez Perce, who were very fond of the many gifts the expedition brought. During this period, although the expedition members ate well, many became sick again.

On October 6, Lewis and Clark resumed traveling on waterways. After branding their horses, the expedition left them with the Nez Perce, who promised to hold the horses until the expedition returned. (Of course, the Nez Perce were hoping the expedition would never return and they would get to keep the horses.) Now traveling the Columbia, the expedition met with whitewater rapids. Along the way, Native Americans observed the explorers. Once, a group brought a prisoner they believed was Shoshoni, but Sacajawea was unable to communicate with her.

With winter coming, Lewis and Clark now began searching for a place to make camp to wait out the cold months. The Shoshoni guide, Toby, continued to help the expedition make its way down the river, and on November 8, 1805, the group sighted the Pacific Ocean. On December 7, the group started building a winter base called Fort Clatsop. By January 1, 1806, they completed construction of the fort, and prepared for the long winter.

Coming out of the mountains past Nez Perce territory, the rivers the expedition followed were now flowing west, out to the Pacific Ocean. As a result, the men moved downstream and traveled at a much faster pace than before. Despite the speed of travel, there was a great deal of trouble still awaiting the explorers. While the expedition had to deal with whitewater rapids, various Native American groups observed them from shore. Again, it was probably only the presence of Sacajawea and her baby (Jean Baptiste) that saved the expedition from getting involved in any serious conflicts. As they continued down the river, curious Native Americans paddled out their canoes to have a look at the explorers. Clark would note how incredibly skilled canoesmen the Indians were.

Although no hostilities with the Indians arose, Lewis and Clark found themselves in trouble in matters of trade. All that the Indians of the West Coast seemed to want were blue beads, and the expedition had already traded all of their blue beads away. Cursing themselves for not bringing more of the beads, which were cheap in the East, Lewis and Clark went to Sacajawea, who selflessly surrendered her belt, which was covered in them. The captains traded these last blue beads for an otter-skin robe, and also paid Sacajawea for her sacrifice. Another trade difficulty arose when many of the Native American girls in the region began coming to the camp trying to trade sex for goods. Lewis and Clark discouraged this, because they feared the expedition would be hit by an epidemic of venereal disease; these same Native girls consorted with sailors who landed on the West Coast. However, as the expedition journals indicate, not all of the members of the expedition heeded their commanders' advice.

Once at the Pacific, it proved difficult to find a campsite. The Columbia's water was now brackish (semi-salty), and fresh, drinkable water became harder to find. But Lewis and Clark were nonetheless very democratic about choosing the site: everyone, including Sacajawea and Clark's African-American servant York, received a vote. Ultimately the point they chose (Clatsop) was on the South Side of the Columbia River, where the animals were more abundant and the hunting better.

Sacajawea put up with the harsh winter without complaining. Her stoicism in accepting misfortune and difficulty without protest impressed Lewis, who called Sacajawea's manner "either philosophy or folly."