Neil Patrick Harris gets to say his famous catchphrase from How I Met Your Mother (2005) when he is challenged to a duel by Albert: "Challenge accepted!" However, neither of the writers knew this when they were writing the movie, and later during test screenings they didn't know why audiences were laughing.
The genesis of the film can be traced to an inside joke by Seth MacFarlane, Alec Sulkin and Wellesley Wild. The three mentioned how the Wild West was always depicted to be dangerous and believed that there are too many ways to die in the setting.
During his pow-wow with the Indians, Seth says "mila kunis" in Native American speak. The translation below reads "fine." Mila Kunis plays Meg in Family Guy (1998). She was also in Ted (2012), another Seth MacFarlane film.
One sign in town in the movie reads "Windisch and Sons". This is an ode to Christopher Windisch, the film's construction coordinator, and his son, who was the labor foreman on the film's set construction crew.
Halfway through the film, when Albert and Anna are sitting on a log talking, a tornado appears to their right. It's a subtle reference to the film's title, something else that could kill you in the West.
Ryan Reynolds plays the bar patron who is shot by Clinch. His appearance in this slightly mimics his role in Ted, in which he basically had a gratuitous cameo. In the commentary for Ted Seth Macfarlene said it was funny because they basically waste Ryan Reynolds, in the fact that he has almost no role or speaking lines, which is what he has in this.
The scene were Anna puts a daisy in Clinch's bottom is similar to a classic scene in Carry On Nurse (1959), where Wilfred Hyde White is a patient who has been annoying the nurses, so instead of inserting a rectal thermometer in his bottom, they put a daffodil.
At the start of the movie, where the narrator talks about the different ways the Wild West could kill you, a picture of a dead man under a white sheet is shown around the time the narrator mentions, death from "disease". The picture used is actually that of the corpse of a train robber by the name of Cole Estes (a.k.a., Cole Younger) shortly after he was shot to death by a U.S. Marshal. The marks on his face are actually gunshot wounds.
Director Trademark: (Family Guy): Seth Mcfarlane, who plays Albert, voices Peter, Brian, and Stewie Griffin. Alex Borstein, who plays Millie, voices Lois Griffin, Loretta Brown, and Tricia Takanawa. Mila Kunis is mentioned, who voices Meg Griffin.
Both Gilbert Gottfired and Christopher Lloyd also had roles in the PBS children's maths educational series, Cyberchase where Gottfired plays the Cybersquad's ally Digit while Lloyd plays antagonist The Hacker.