In the Undead Nightmare DLC, there is a trophy/achievement called "Six Years In The Making." For the achievement, you have to "Find and kill a Sasquatch." The title of the achievement is a reference to Grand Theft Auto San Andreas where there is a popular myth that Bigfoot exist in the game.

In Blackwater's Cemetary is a grave that reads "Clinton Underwood". This is a reference to the actor Clint Eastwood, who played parts in many westerns.

Many of the cemeteries within the game contain grave markers with humorous epitaphs.

In South Korea, due to a lack of dubbing and translation with many games, titles like Red Dead Redemption and Metal Gear Solid 4: Guns of the Patriots come with a guide to read which translates the script from the game.

Because of a glitch, throwing dynamite or Molotov cocktails while locked-on in Dead Eye mode will result in the explosive homing in on its target no matter where it is.

The oil-drilling project in New Austin named Plainview is likely a reference to the character Daniel Plainview, played by Daniel-Day Lewis in the 2007 film There Will Be Blood. The character is, appropriately, a ruthless oil baron and tycoon operating in the South-Western United States in the opening decades of the 20th century. The foreman's building in Red Dead Redemption matches the one used in the film, and the man often found working at his desk in the office bears a striking similarity to Plainview himself.

There is a theory that the main character, John Marston, has a weakened or blind left-eye. Evidence supporting the theory is Marston's "Deadly-Assassin" outfit which includes an eye-patch that goes over his left-eye, during cut-scenes Marston seems to turn his head over to the left slightly to possibly see more with his right eye, sometimes when using Dead-eye, Marston will comment "I think like I got my eye back", after Dutch Spoiler:shoots the woman during Great Men Are Not Always Wise, John does not take the opportunity to shoot Dutch as he runs through the doorway on John's left side. The other lawmen make a comment towards John about not shooting him, too.And the Undead version of John Marston has a missing left-eye.

There's also another interesting bit hinting at this, which is a comparison between John Marston and Johnny Klebitz from Grand Theft Auto IV; Both share similar names (John/Johnny), both rode in gangs that left them both for dead and come from rough (and criminal) backgrounds, both have antagonists named Bill/Billy, both had a girlfriend/wife that was considered "every man's", both are forced to work with the government to save themselves and those they care about, and it is implied Johnny has a weakened/blind eye. ("Oh. I should use my good eye.")

The achievement/trophy "Fightin' Around the World", which is earned by knocking out a person in each saloon in the game, is a reference to the South park episode The New Terrance and Phillip Movie Trailer, which includes a television show called Fightin' Around the World with Russell Crowe.

John Marston and his wife Abigail Marston share the same names as the second President of the United States and his wife, John Adams and Abigail Adams. Both families also had a son named John as well ("Jack" is a diminutive name for John) and both had a daughter die very early in their life.

The "Undead Hunter Outfit" found in the Undead Nightmare DLC strongly resembles the one worn by the character Ash in the movie "Army of Darkness". This is very likely a reference to the film, as the name of the outfit changes to "Army of the Undead" once the player is able to finish the game's story.

The final story mission, Spoiler:"The Last Enemy That Shall Be Destroyed" is a reference to a line in the Spoiler:fifteenth chapter of the First Epistle of Paul to the Corinthians: "The last enemy that shall be destroyed is death."

There is a chance that the death scream of an enemy will be the "Wilhelm Scream", a notable scream used in numerous action movies.

The Elegant Suit was originally planned to be worn without a hat, similar to the Gentleman's Attire.

A very early Duster Coat outfit can be seen in the 2005 teaser for the game. It appears to be lighter in color, and has a cut in the back, similar to the final outfit.

There are unused wanted posters for John Marston and Abraham Reyes in the game's files. These may have been placed around the map at some point. However, the Reyes poster is very different compared to the other posters.

There are multiple cut bounty posters in the game's files.