During the Cowboy/Putter changeover, Robert Picardo had to do quite a bit of work. After Putter has been changed, we see Lydia asking how he got into the room, etc. The first time Robert goes off screen he's actually rushing behind camera, tearing off his breakaway clothes and getting into the bath. A make-up assistant is behind a fake wall at the head of the bath, having just changed the Putter Wig to the Cowboy one. Before the Scrimshaw meeting, Picardo's voice was overdubbed with Short's. During the meeting, Picardo used his own voice (with a Short-esque lilt), as the filmmakers didn't think Short "trying" the Cowboy's voice would be convincing enough to make the scene work.
When filming the meat truck scene with Scrimshaw and Jack, the director realized only that day that Scrimshaw had no lines prepared; the script only contained Tuck Pendleton's voiceover. They hastily wrote a speech for Kevin McCarthy on a piece of paper, although in the film itself Tuck's voiceover renders the monologue inaudible. In the DVD commentary, Joe Dante says the speech was wonderfully amusing, but the piece of paper was lost before the lines were copied elsewhere.
John Hora who had previously worked as Joe Dante's cinematographer on all of his movies, was cast as Ozzie after Steven Spielberg suggested him to play the absent minded professor. Director Dante and Producer Michael Finnell were very skeptical about that idea and Spielberg insisted that they give him a screen test to just to see and was cast after impressing Dante and Finnell.
After Scrimshaw and Canker are shrunk 50%, there are a few scenes where they are seen with full-size actors. These shots were filmed using forced perspective. For the car scene, the rear of the car is actually twice as large as a normal car rear, and was about 20 feet away. During the scene half size hands and double-size heads were used. Using this method, the film-makers didn't have to worry about compositing two separate shots in post production, so the shots could be completed quicker. Even in the final scene with the suitcase, the case was twice as large, but the hand that closes it was real, closer to the camera in sync with the closing. (It took about 20 takes before it was perfect.)
Luca Bercovici was the original actor to play Igoe and his scenes were shot, but was replaced because the producers felt that he was not an intimidating villain as he was about the same height and body size as Martin Short.
When they are shrinking Tuck Pendleton, the lab's instrumentation shows a reading on the screen that is six interlinked hexagons (two top, three bottom). This is the symbol that the "Combined Minature Deterrent Forces", or CMDF, also used in the movie Fantastic Voyage (1966).
The filmmakers used two different shopping malls for the scene where the doctor injects Tuck into Jack's rear. The opening scenes where the doctor runs in and heads for the elevator were shot in the Northridge Mall in the San Fernando Valley in Los Angeles (also the epicenter of the '94 quake). The scene where he reaches the top and rams the syringe into Jack was filmed on the top floor of the Sherman Oaks Galleria, another mall several miles away.
This was the first film commercially released in Dolby Stereo "Spectral Recording" (SR). SR is a vastly improved noise reduction system which replaced Dolby's original "A-type" noise reduction used for decades in all professional analog recording mediums (including all previous Dolby Stereo movies).
Director Joe Dante originally turned this movie down when it was written as a sci-fi spy movie. After making The Explorers (1984) the story was rewritten as a sci-fi comedy. Dante was interested once one of the writers reworking the script said, "Imagine if someone like Dean Martin is put in a space pod, miniaturized into a syringe and injected into the body of someone like Jerry Lewis." He changed his mind, but the script was given to executive producer Steven Spielberg who offered it to director Robert Zemeckis. Zemeckis didn't want to make it, so Spielberg offered it to Dante who accepted.
The first cut was overwhelmingly positive by the crew and Warner Bros. executives. They were very excited to release it and hoped it would be their biggest movie for the studio just like when Dante and Spielberg made Gremlins (1984). Though they released it on independence day weekend, it had little advertising and flopped.
Mel Gibson, Kevin Costner, Patrick Swayze, Tommy Lee Jones, Jeff Bridges, Richard Gere, Michael Douglas, Harrison Ford, Bruce Willis, Arnold Schwarzenegger, Sylvester Stallone, Michael Keaton, Tom Hanks, Jack Nicholson, Robert De Niro, Al Pacino, Michael Nouri, Jeff Goldblum, and Kurt Russell were considered to play Lt. Tuck Pendleton.
The lab in the beginning of the film is the polar opposite of that of Victor Scrimshaw's, (Kevin McCarthy's) later on in the film. The lab seen when Dennis Quaid is miniaturized is in fact what a real lab would look like which is basically a poor man's miniature home made pod. While the one later on seen during the scene where Ingoe (Vernon Wells) is miniaturized and injected into Martin Short is more high tech with all of the latest industrial tools with proper funding.
The novelization for another Steven Spielberg produced film, Young Sherlock Holmes (1985) foreshadowed this one with the mention of digestive juices. Also, both Holmes and Tuck Pendleton get the line "we're in this together".