On August 25, 1804, while their three boats proceeded upriver, the two captains and several men went ashore near the mouth of the Vermillion River in present southeast South Dakota to visit a hill which the Indians of the vicinity insisted was haunted by evil spirits. Moving on upstream past the mouth of the James River, they paused from August 28 to 31 at the Calumet Bluff on the present Nebraska side of the Missouri to council with the Yankton Sioux, the first of this numerous tribe and the first of the truly nomadic Plains Indians they had met.

The captains were pleased with the council, but as they moved on they were increasingly anxious about George Shannon, the youngest member of the Corps of Discovery, who had been missing since August 27, when he was sent out to locate two stray horses. Mistakenly believing that the boats had gone ahead of him, Shannon hurried up the river trying to overtake them, although they were actually behind him. Not until September 11 did they overtake the young man, now weak from hunger.

The party was now entering the semi-arid High Plains, previously unknown to Anglo-Americans, and they were encountering some of the region's characteristic plant and animal species. In present northeast Nebraska they first saw a prairie dog "town" and obtained a specimen of that animal. In modern South Dakota, as September wore on, they also discovered the coyote, the pronghorn, the mule deer, the jackrabbit, and the magpie.

Some miles north of the White River, on September 16 and 17, they paused for two days to rest, dry out their baggage, and perhaps to make some decisions. From the first, the captains had intended to send back, before winter, a small party of men carrying dispatches, journals, and specimens to be shipped to President Jefferson. They had never found an opportune time, and it was here that they decided not to send out the return party until the following spring. Lewis wrote several pages of journals during the two days halt, the first such daily journal-keeping he appears to have done since May.

Leaving the rest camp, they traveled around the remarkable "Grand Detour" of the Missouri River and arrived on September 24 at the mouth of the present Bad River, which they called the Teton, for it was there that they met a large number of the Teton Sioux. Here they had their first really hazardous and potentially violent encounter with Indians on the journey, arising from the arrogance of some of the chiefs, disagreements among the Sioux leaders, and very likely confusion resulting from the lack of a Sioux interpreter. The Sioux attempted to bully the Corps of Discovery as they did trading parties, but the captains were not prepared to submit. As they saw it, they represented the dignity of the United States, and their pride and a military conception of security required that they show a readiness to fight. Rightly or wrongly they believed that the Tetons planned a surprise attack on their boats and they remained uneasy until they left those bands behind.

A few days later, on October 8, they reached the villages of the Arikaras in what is now northern South Dakota. Their reception by these sedentary farmers was far more encouraging than that of the Tetons, and the party remained until the eleventh. The captains hoped to serve as peacemakers between the Arikaras and the Mandans and Hidatsas farther upriver and as they departed they took an Arikara chief with them to act as ambassador to the two tribes. On October 13 Private John Newman was arrested and tried for "having uttered repeated expressions of a highly criminal and mutinous nature"; the verdict was guilty and he received seventy-five lashes and was dishonorably discharged, although he remained with the party until spring doing hard labor. Newman was repentant, but the captains refused to reinstate him.

The party arrived on October 25 at the Mandan and Hidatsa villages, 164 days and about 1,510 miles out from Camp Dubois. Here they were met with a mixed reception and informed the Indian leaders of the change in official sovereignty. Winter was near and the Indians and various white traders told the captains that the Missouri would soon freeze; they decided, therefore, to discharge some of their French boatmen and make their winter quarters in the vicinity of these friendly tribes, from whom they could obtain corn to supplement the results of their hunting. On November 3 the party began the construction of Fort Mandan, on the eastern side of the Missouri a few miles below the mouth of the Knife River in west-central North Dakota and nearly opposite the lower Mandan village.

The stockaded log fort would be their home for five months, during a bitter Northern Plains winter in which temperatures sometimes dropped to over forty degrees below zero Fahrenheit and venturing outside was likely to result in frostbite. Nevertheless, Clark describes the party as being in good spirits. It was by no means a period of idleness, although Lewis notes playing backgammon at least once. Hunting, in spite of the fierce cold, was frequently necessary to provide meat. Indians visited the fort constantly and the chiefs, at least, expected to be entertained by the captains. The smiths were kept busy making tomahawks for the visiting warriors, in exchange for corn. The men visited the villages regularly and some of them contracted venereal disease as a result.

For the captains the period was occupied not only with diplomacy but with attempts to counter Sioux attacks on the village tribes, with preparations for continuing their journey in the spring, and with evaluating what they had already learned. Traders and Indians provided information that went into the large map of the West that Clark prepared, still largely conjectural beyond Fort Mandan but now incorporating Indian information about rivers and mountains west to the continental divide. The Mandan and Hidatsa villages were a center of intertribal trade, and the captains met members of the Cheyenne, Assiniboine, and Cree tribes.

Soon after the Corps of Discovery settled in for the winter, more traders arrived from Canada representing the competing Hudson's Bay and North West companies. The captains had no objections to the British engaging in legitimate trade with the Indians on what was now American soil, but they suspected that the traders were trying to win the political allegiance of the village tribes away from the United States. The traders consistently denied such intrigues, but the Americans were not convinced and even believed that the British were trying to sabotage the expedition itself.

At Fort Mandan other persons were added to the party. Toussaint Charbonneau, an independent Canadian trader living at one of the Hidatsa villages (now called Sakakawea), had two Shoshone wives, natives of the Rocky Mountains along the continental divide and later captives of the Hidatsas. Charbonneau hired out his services and those of his consorts as interpreters for the trip across the mountains; in fact, only one of his wives, Sacagawea, who gave birth to a son during the winter, actually made the trip. In time she became the most famous member of the party after the two leaders themselves. Baptiste Lepage, another Frenchman living with the Mandans, also joined up as an enlisted soldier to replace Newman.

In March the ice began breaking up in the Missouri, and the Corps of Discovery started preparations for a departure in early April. Having decided to send the keelboat back to St. Louis with the returning soldiers and discharged engagés, they built several new canoes from cottonwood logs and prepared specimens, journals, and maps to send back to Jefferson, including a live prairie dog and several live birds. The permanent party now consisted of the two captains, three sergeants, twenty-three privates, Drouillard, Charbonneau, Sacagawea and her infant, and York. Up to Fort Mandan the route had been known to whites and even mapped to some degree, but now the party faced a long journey through country known only in part from sketchy Indian information. Just five weeks short of a year after leaving Camp Dubois, they set out on April 7, with still half a continent to cross before they reached the Pacific.