The miniseries begins in the 1820s and is told mainly through the third person narration of Jacob Wheeler (Matthew Settle) and Loved By the Buffalo (Joseph M. Marshall III), although episodes outside the direct observation of both protagonists are also shown.

The series features well-known performers including Josh Brolin, Gary Busey, Michael Spears, Tonantzin Carmelo, Skeet Ulrich, Garrett Wang, Steve Reevis, Rachael Leigh Cook, Wes Studi, Irene Bedard, Alan Tudyk, Christian Kane, Russell Means, Jay Tavare, Keri Russell, Graham Greene, Sean Astin, Beau Bridges, Judge Reinhold, Zahn McClarnon, Tom Berenger, Gil Birmingham, David Paymer, Raoul Trujillo, Eric Schweig, Lance Henriksen, Simon R. Baker, Tyler Christopher, Tatanka Means, Gordon Tootoosis, Sheila Tousey, Annabella Piugattuk, and Will Patton.

Loved by the Buffalo's sister, Thunder Heart Woman (Sarah Weston), is married off to a white trapper, Thomas Lebeck (Scott Heindl).

Dog Star (Michael Spears) and Running Fox (Zahn McClarnon) marry two sisters and begin families, but Loved by the Buffalo realizes that his destiny lies on a different path.

Jacob accompanies Smith's party to California, where they are arrested by the Mexican Capitan de Salamanca (Francesco Quinn) for trespassing and held at the San Gabriel Mission.

Thunder Heart Woman's (Tonantzin Carmelo) trapper husband Lebeck is killed in an attack by the Crow, her infant daughter is captured, and she is sold into slavery.

Loved by the Buffalo takes Jacob and Thunder Heart Woman to a sacred hilltop where a stone medicine wheel has been erected and tells him about the four great powers that it symbolizes.

After living in Wheelerton for a time, Jacob decides to take his family, now including a young son Abraham High Wolf, back west.

Among the other settlers is a German immigrant preacher named Hobbes (Derek de Lint), a free black family fleeing racial prejudice, and several former mountain men.

While working at the Wheeler ranch, now dubbed Rancho Paradiso, Jethro encounters a 49er named Martin Jarrett (Sean Astin) who brings him the first news about the California gold rush.

An anti-slavery Unionist himself, Samson allies with the abolitionist Jayhawkers during the days of "Bleeding Kansas" as tensions rise in the months leading up to the Civil War.

He refuses to leave the town despite being threatened by Border Ruffian leader Bloody Bill Anderson (Christian Bocher) for hiring Henry Foster (Kwesi Ameyaw), a black worker.

Dog Star's son, Brings Horse (Nathaniel Arcand) is shot by an army sniper when he climbs a telegraph pole to investigate the wires strung from the top and cutting them.

In March 1864, while photographing California Governor Frederick Low, Ethan Biggs and his wife, Margaret Light Shines (Jacob's daughter), decide to see the Indian Territory, and they take a stagecoach to Denver.

On September 28, 1864, Black Kettle holds council with Colorado Territory Governor John Evans, Colonel Chivington and Major Wynkoop (Arron Shiver), to ensure peace.

Margaret and Ethan decide to continue their journey, but, on November 29, 1864, the night before they have planned to leave, Colonel Chivington attacks Black Kettle's village at the head of the Third Colorado Cavalry.

Despite the treaty, Col George Armstrong Custer (Jonathan Scarfe) and the 7th Cavalry attack Black Kettle's Cheyenne village at the Battle of Washita River on November 27, 1868.

The Black Hills are considered by the Lakota to be the axis mundi, or center of the world, and the 1868 Treaty of Fort Laramie granted the Indians ownership of the mountain range.

Robert Wheeler is operating a general store in Hillsgate, Dakota Territory, while Clara spends her spare time teaching the town's children.

Margaret Light Shines (Irene Bedard) has been a prisoner of the Army since the Battle of Washita River, but she finds purpose helping the women and orphaned children at the same Indian Reservation as Red Cloud.

In 1879, Richard Henry Pratt returns to Hillsgate, and invites Robert and Clara to join him in teaching at an experimental school in Pennsylvania designed to "civilize" Native American children.

Voices That Carry's numerous attempts to undermine the process upset Pratt, but Robert tries to convince the boy to work hard so he can record the story of his people.

After 6 months in Carlisle, Robert falls out with Pratt over his strict teaching methods, and heads back for home with Clara, who is now bearing their second child.

Indian Agent Daniel Royer (David Paymer), fearful of the Ghost Dance, sends for help and Colonel James W. Forsyth arrives with the 7th Cavalry Regiment.

The 7th Cavalry regiment moves outward from the reservation into the hills and valleys restricted of Indian settlement where Big Foot (George Aguilar) and his followers are hiding out.

Jacob Wheeler (John Terry) and his wife Thunder Heart Woman (Sheila Tousey) decide to move to South Dakota to settle in with the people they care about—Robert and Clara.

Margaret Light Shines walks past and sees a missing person search notice (put up by Robert) and realizes her family is nearby.

While Big Foot's men rush to pick up their weapons and defend themselves, the women and children run in opposite directions only to be mowed down by the 7th Cavalry's gunfire.

"So long as there are still a few Lakota left who understand the traditional ways of their people, the tribe, history, and the memories and lessons of our past can still be preserved so that future generations may also learn from them."

The final scene shows Loved By the Buffalo sitting with a group of Lakota children, Margaret, and Thunder Heart Woman, teaching them the past of the people and his own experiences.