Smith has released little information about the film, except that it is a comedy about two lifelong platonic friends who have managed to trudge into adulthood with a satisfying lack of accomplishment. However, a high school reunion and dire rent problems spark the novel moneymaking idea of pulling together an amateur porn enterprise with their friends. As the film begins shooting, however, Zack and Miri realize their feelings for each other might be more than just that of friends.

The film began shooting in Pittsburgh on January 16, 2008, with a projected release date of October 31, 2008. Shooting concluded on March 12, 2008.

This is the first Kevin Smith film produced without any rehearsal time prior to shooting. In all of Smith's previous films, actors were made to participate in rehearsals lasting between one to three weeks in an effort to fine-tune performances before production even began. Smith attributes this lack of rehearsals to his confidence in the quality of his actors.

The Motion Picture Association of America initially gave the film an NC-17 rating for "some graphic sexuality". Smith appealed the rating, hoping for an "R" rating, and the film was viewed by the MPAA again. In an interview with MTV.com, Seth Rogen commented "It's a really filthy movie. I hear they are having some problems getting an R rating from an NC-17 rating, which is never good". He continued, complaining that "They [fight against] sex stuff. Isn't that weird? It's really crazy to me that Hostel is fine, with people gouging their eyes out and shit like that... But you can't show two people having sex -- that's too much". On August 5, the rating was successfully appealed to an R with no cuts. It attained the rating for "strong crude sexual content including dialogue, graphic nudity and pervasive language".

A song by the band Live, entitled "Hold Me Up", which Smith has said he has been trying to use for over 13 years, appears in an "emotional scene" with Zack and Miri. Smith made a statement about featuring the song in the movie:

It's an old song that I first heard in '95, when we were putting together the Mallrats soundtrack. It was actually in the film for the first test screening, but Live decided they wanted to hold onto it as a potential single off their next album (which would follow Throwing Copper). When I was editing Jay and Silent Bob Strike Back, the song had still never surfaced or been released, so I put in a request for it again. Again, I was denied. Third time, apparently, was the charm. Needed a song for that sequence in Zack and Miri and remembered the Live track. This time, the band signed off on us using the track. Took 13 years, but was worth the wait.

Although the lead role was written for her, Rosario Dawson did not take part in the film, as she was doing Eagle Eye at the time.

The November 16, 2007 issue of USA Today confirmed that the roles of Zack and Miri will be played by Seth Rogen and Elizabeth Banks.

In January, Smith revealed that Tyler Labine, Katie Morgan, Craig Robinson, Traci Lords, Jeff Anderson, Jason Mewes, and Ricky Mabe will have supporting roles in the film.

Justin Long and Brandon Routh both make appearances in the movie as a gay porn actor and his partner respectively, with Routh being uncredited.

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