Warner Bros. Feature Animation was in serious financial trouble during the film's production, and in 2000 it came down to two options: green-light another film by Brad Bird, who made the critically acclaimed film The Iron Giant (1999), or this film. Warner executives chose this film over Bird's, and upon learning this Bird got so mad that he took his film with him to Disney and Pixar. That film would become the highly successful The Incredibles (2004), whereas this film bombed at the box office, was critically panned, and ultimately killed Warner Bros. Feature Animation.
Bill Murray's character mentions a "National Chicken Wing Festival" in Buffalo, New York. While the festival did not exist during the filming of the movie, this mention caused organizers to create an annual festival in Buffalo.
At 01:01:04 into the movie, Osmosis Jones walks into the Chief's office and says "Brandy! I mean, Leah. Why are you here?" He is speaking to the mayor's aide Leah, who is voiced by Brandy Norwood. The flubbed line was acted so well that it was left in because it felt pleasingly funny.
The dreams that Frank has in the order they are seen are: "Honey, I forgot my pants"; "The Exam" with disclaimer "He didn't study... and the test is in five minutes!"; "Your Worst Nightmare" with Uncle Bob marrying Shane; "Girls from the bus stop".
Nerve News Network (NNN) is a parody of Cable News Network (CNN), especially in its logo. CNN is owned by TimeWarner, the same media conglomerate that owns Warner Bros., the major Hollywood film studio that produced this movie.