The year is 1827. In Virginia, young Jacob Wheeler dreams of adventure. Leaving his family behind, he joins renowned mountain man Jedediah Smith on an expedition to California. Meanwhile, a young Lakota holy man, Loved by the Buffalo, receives disturbing visions about the coming of the white man and the demise of the buffalo. When his sister, Thunder Heart Woman, is saved by Jacob, the lives of the two families become forever intertwined.

The changes in the western frontier take their toll on the Native people. Some choose to cast their lot with the white man, while others cling to their traditional ways. Jacob Wheeler and his wife, Thunder Heart Woman, return to Virginia, but soon the promise of a new life in California entices Jacob to set out again along with his brother Jethro. The road is long and hard. Many are lost, and in the end, one brother makes the ultimate sacrifice.

Gold fever spreads throughout the land bringing thousands of prospectors to California, and leaving a wake of destruction across Lakota sacred land. Greed overtakes Jethro Wheeler, who risks his life to strike it rich. In exile, Loved By The Buffalo continues to seek the prophet who will save the Lakota and their land. Meanwhile, back east, the election of President Abraham Lincoln divides the Union.

The race is on as the Central Pacific and Union Pacific Railroads lay down track across the U.S. bringing east and west together. Jacob Wheeler's one son, Abe, joins the railroad crew, while his other son Jacob Jr. becomes a scout for the army. Jacob's daughter Margaret and her photographer husband are captured by the Cheyenne, but her Lakota heritage saves them and they are adopted by the tribe. When the village is attacked by overzealous U.S. soldiers, many are murdered. Witnessing the brutality, Margaret decides to stay with her Cheyenne family.

Loved By The Buffalo believes he has found the foretold prophet when a mysterious Indian named Wokova inspires his people with the Ghost Dance and a vision of their restored land. But the ritual stirs up more fear among those who wish to contain the Indians. Sitting Bull is “accidentally” killed, further inciting the Ghost Dance rebellion, which in turn, leads to more brutality toward the Indians. As the circle closes, Loved By The Buffalo and Jacob meet again. Reunited with his family, Loved By The Buffalo resolves to pass on his Lakota traditions to the next generation so that their ways continue to live on.