The game largely did not have a traditional script, and a lot of Deadpool's dialogue was improvised by his voice actor Nolan North, who reacted in-character to the actions happening on-screen. For example, the idea to have Deadpool call North over the phone to unsuccessfully pitch a voice role for a game and insult himself was a suggestion by the actor himself.

Deadpool's ability "I Know Gun-Fu" is seemingly inspired by a scene from the 2002 film "Equilibrium", where Christian Bale's character John Preston gets into a shootout at a traffic stop. The momentum attack that Deadpool can use with this ability, "The Equalizer", causes him to rapidly move his arms around to fire his twin guns at two targets at the same time in a similar way to how Preston fires his pistols by the end of the shootout.

During the level Landed in Prison where Deadpool has to go save Rogue, the white textbox (who is later revealed to be Spoiler:Madcap in the comics) and yellow text box have this exchange:


At the time of the game's release, Rogue lost her ability to fly. Not only is it poking fun at established canon, but indirectly references X-Treme X-Men Volume 1, Issue #13. In this issue, during a fight with the villain Vargas, he stabs Rogue, and this causes her to lose her superpowers, including flight.

In Deadpool's apartment, going near the stove allows him to make hundreds if not thousands of pancakes in one sitting while commenting: "I love the smell of pancakes in the morning. ...smells like victory!" This scene is lifted from an issue of the 2008 Deadpool comic series (volume #2, issue #16), in which Deadpool makes 372,844 pancakes so Domino has a cushion to fall on. The quote itself is a reference to a scene from the 1979 film "Apocalypse Now". Daniel Way wrote both this issue, and this game. The artwork for the game's disc is also a paper plate with a pancake on it referencing this scene.

In 2015, GameSpot published a now-deleted listicle covering 20 video games with the most expensive budgets, claiming that Deadpool was made on an estimated budget of $100 million dollars. However, former High Moon Studios and Activision employees have since disputed this number as being false, and it is believed to have originated from a running gag within the game in which Peter Della Penna, the real-life president of High Moon Studios, complains about Deadpool frequently going over budget. Their then-manager of licensed games Chris Baker stated: "I wasn't privy to the actual budget, but $100 million is GTA-level money, at least back then." Former Activision marketing director Vicharin Vadakan also claimed that Activision "barely had any" budget for the game's marketing, forcing them and High Moon Studios to produce trailers in-house, and called it one of their more cost-effective campaigns.

The Deadpool video game was originally announced in 2012 as a game based on Hit-Monkey, a different Marvel character created by Daniel Way (who would be the writer of the Deadpool game). However, a man in-character as Deadpool crashed the Hit-Monkey game's panel at the 2012 San Diego Comic Con to reveal that it was a red herring, and debuted a teaser trailer. After the convention, on November 27, 2012, an article appeared on Marvel's website written from Deadpool's perspective confirming the game's development and joking that he took over the development of the game.

The scene where Deadpool dances with Death in his apartment is similar to how John Travolta's and Uma Thurman's characters danced in the 1994 movie Pulp Fiction. The scene also includes a subtle joke about a burger with a French sounding name, referencing a famous line from the same movie.

During the development of the game, High Moon Studios announced a contest that would allow the winner to appear in game. The winner was Bill Salina, a database administrator from Atlanta, Georgia. He appears as the character Storm Thrower, who as he is attacked will name off pizzas.

Deadpool had a different costume in the teaser trailer.

During level 3, in the sewers you can find a pizza with a sai stuck into it. This is a reference to the Teenage Mutant Ninja Turtles.

At Deadpool's Surprise Party in Chapter 5, Gambit is playing the keyboard in the far corner. This marks his only actual appearance in the game (not counting all the failed clones based on him).