Series creators Trey Parker and Matt Stone wrote 850 pages worth of content for South Park: The Stick of Truth, but Obsidian Entertainment urged them to cut out material due to their scope being deemed overambitious, with Parker jokingly tracking the release of the game to "holiday season 2032". Some ideas included plot lines involving the Vamp Kids, Corey Haim Spoiler:(Michael Jackson), and Nathan and Mimsy appearing as friends the player could add. While all these characters were cut, the Vamp Kids make cameo appearances among Clyde's Army of Darkness. When the suggestion to add these characters and plots via downloadable content came up, Parker rejected the idea. Some of these storylines would find themselves into the show via the episodes "Black Friday", "A Song of Ass and Fire" and "Titties and Dragons". The game's sequel South Park: The Fractured But Whole would incorporate the Vamp Kids and Corey Haim, and Nathan and Mimsy via the "From Dusk Till Casa Bonita" and "Bring the Crunch" DLC packs.

According to the commentary for the South Park episode "Insecurity", one of the ideas for the game would have been to sneak into other people's homes and get past their security systems. This was before Trey Parker and Matt Stone went with the idea for the RPG Stick of Truth game.

When the game's original publisher, THQ, went bankrupt, South Park's creators didn't know about it until reading about it in the news. They were really excited when they heard that Ubisoft had picked up the rights to the game.

The achievement/trophy "Heisenberg" requires the player to defeat the Meth Tweekers while wearing the Evil Cartman goatee and the bald cap. This is a reference to the TV series Breaking Bad.

Several scenes, mostly involving abortions and anal probing, were censored in the European console releases. Instead of simply removing the scenes, these sections of the game are replaced by a picture of Michelangelo's David face-palming in front of a European flag, with descriptive text of what the scene would have entailed.

The scenes are also censored in the Australian release, and instead feature a picture of a crying koala.

The PC release, however, was only censored in Germany, Austria, Australia, Singapore, Hong Kong & Taiwan, with all other regions, including the UK, receiving the uncensored version.

Matt Stone and Trey Parker have stated that The Elder Scrolls V: Skyrim, Earthbound, Paper Mario, and The Legend of Zelda were all key influences to the direction that The Stick of Truth took. Parker said that he loved the feeling of Earthbound, in being a kid in a big world, and playing within something larger than initially perceived.

Attempting to leave the room when confronted with the task of Spoiler:removing a Snuke from Mr. Slave's asshole will cause Spoiler:an explosion to occur, the credits to play, and results in the player receiving a game over.

Certain elements from the game were mentioned in Gameinformer, but never made it into the finished product of the game. Some of them were reworked and scrapped all together. There were plans for showing the kingdoms of the Underpants Gnomes and Crabpeople, fighting hippies, a sidemission where the new kid has to rescue Cartman's Polly Prissy Pants doll from the ginger kids, and an enemy dragon (that may have been a boss at one point in the game) called The Thing.

It's possible to use the Mr. Slave summon while Spoiler:you're inside of him.

The Elf Blade is a possible reference to Link's Master Sword from The Legend of Zelda series.

The Bank Teller from the season 13 episode "Margaritaville" is a secret optional enemy in the game. The New Kid simply needs to use Gnome Dust to shrink down and go through a well hidden hole behind the left of his desk in the bank. The Bank Teller is ridiculously easy to fight, as he has no Shields, Armor, and no Special Attacks. His melee attack consists of kicking the New Kid or his buddy. Once defeated, the New Kid can loot him for all the money that was invested into him over the course of the game, as well as an extra $10 for each $20 invested. After defeat, The Bank Teller remains unconscious until the player leaves the bank, at which point he'll despawn like any other enemy.

If you enter New Kid's room while Stan is your buddy, he will take note of the goldfish saying: "Nice goldfish. I had to get rid of mine after it killed a bunch of people." This is a reference to the season 2 episode "Spookyfish".

If the New Kid enters the bathroom in Stan's house, all of the buddies will remark how his father Randy takes "big shits", and Stan specifically points out he set a world record with its size. This is a reference to the season 11 episode "More Crap", where Randy attempts to break the world record for "the biggest crap ever taken".

The closet in Butters' room contains references to various previous South Park episodes featuring him:

• Butters' hockey mask from the season 5 episode "Proper Condom Use".
• The Professor Chaos costume, first appearing in the episode of the same name from season 6.
• A device Butters as Professor Chaos created to take the cherries out of chocolate-covered cherries, replacing the insides with expired mayonnaise, from the season 6 episode "The Simpsons Already Did It".
• The Eric Cartman memorial from the season 7 episode "Casa Bonita".
• Butters' sparkly pink, tap dancing vest from the season 8 episode "You Got F'd in the A".
• Butters' polka dot pajamas from the season 10 episode "Hell on Earth 2006".
• Action figures of the Council of Nine (Glinda, Jesus, Wonder Woman, Luke Skywalker, Morpheus, Aslan, Popeye and Zeus) from the season 11 three-part episode "Imaginationland".
• Butters' chain from the season 13 episode "Butters' Bottom Bitch".
• Butters' "Texans Vs. Mexicans" costume and a mural during his stint as "Mantequilla" from the season 15 episode "The Last of the Meheecans".
• Vials of "Butters' Creamy Goo" (his semen) from the season 16 episode "Sarcastaball".

The Game Over screen for the game shows three Mormon men standing next to the gates of Heaven. This is a reference to the season 4 episode "Possibly", where it's established that Mormonism is the one "true" religion in-universe.