Little Big Man was the name of an actual historical figure. He was a Native American, an Oglala Lakota, who was a fearless and respected warrior who fought under, and was rivals with, Crazy Horse. He also fought at the Battle of Little Big Horn, a battle which is depicted in this film.
The role of Old Lodge Skins was initially offered to Marlon Brando, who turned it down. Other sources claim Arthur Penn's first choice for the role was Laurence Olivier. When that didn't work out, Richard Boone was slated for the role. When Boone backed out at the last minute, Chief Dan George was given the part and earned an Oscar nomination.
As acknowledged in the film, the self chosen names of many American native tribes simply translate as "the human beings," leading to inevitable difficulties in translating and interpreting certain sayings in their languages.
The main tune played when the the 7th Cavalry were attacking on the Washita River and during the Battle of Little Big Horn is an Irish jig titled "Garry Owen". This song was the official song of the Seventh Cavalry of the U.S. Army - Lt. Col. Custer's cavalry. However, the music is actually a medley which consists of The Garry Owen and St. Patrick's Day.
Paul Scofield was considered for the role of Old Lodge Skins. Curiously, it was not until shortly before filming began that director Arthur Penn thought about using an actual Native American for this role - even though an important point made in Thomas Berger's original novel was that Caucasian actors are hardly ever convincing in such parts.
When Merriweather is forced by the lynch mob to reveal the ingredients of his elixir, he includes oil of cloves. The same was used to alleviate Dustin Hoffman's pain following his torture in Marathon Man (1976).