This film was originally in pre-production in the early 1990s, with Danny DeVito and Meryl Streep set to play Boris and Natasha. Legal problems with copyrights prevented the film being made until several years later.
Fearless Leader (Robert De Niro) says to Boris and Natasha, "You talkin' to me? There's no one else here, so you must be talking to me." This is a reference to his most famous lines in Taxi Driver (1976).
When Fearless Leader is explaining a way to kill a cartoon character a spy asks him "What about that movie Roger Rabbit?" June Foray the voice of Rocky and Natasha starred in Who Framed Roger Rabbit (1988) as the voices of Lena Hyena and Wheezy the weasel.
Rene Russo met June Foray at the film's table reading. By her own account, Russo was very nervous about taking on the role of Natasha Fatale and requested Foray to demonstrate the voice. Foray graciously obliged.
The businesses lining the highways have some rather unusual names. Among them are "Lotta Room Motel", "Pump Her Up" (gas station), "Beefy Buns" (fast food), and (glimpsed briefly through the driver's window of the truck) "Boob Mart".
This was the last film from the Rocky and Bullwinkle franchise, and the last to be a live-action movie until Mr. Peabody & Sherman (2014) was released, and became the first film to be a computer animated film for the franchise.
When Rocky and Bullwinkle arrive at Wossamata U, Keenan Thompson and Kel Mitchell's characters mention how the university has been live-action since 1964, once the show went into reruns. Keenan then turns to Kel and jokes, "That'll never happen to us, right?" To which Kel responds, "Right" as they wink at each other. Ironically, their show "Keenan and Kel" on Nick had just ended a month before the film's release, and went into reruns shortly after.
June Foray, one of the surviving members of Rocky and His Friends (1959), who created the voice of Rocket J. Squirrel, does Rocky's voice for this movie. She also re-created the voice of Natasha (when Natasha is in cartoon form) and her ubiquitous "old woman" voice from the old series, as the voice of the narrator's mother.
As the Oklahoma cop is arresting Karen Sympathy, Rocky protests, "But she really is with the F.B.I.!" The cop responds, "Yeah, and I'm really John Goodman." This is an inside joke, because John Goodman is actually playing the cop.