The film stars Muppet performers Dave Goelz, Steve Whitmire, Jerry Nelson, Bill Barretta, and Frank Oz, as well as Jeffrey Tambor, F. Murray Abraham, David Arquette, Josh Charles, Hollywood Hogan, Ray Liotta, Rob Schneider and Andie MacDowell.

After an alien species appears to be trying to send a message through his bowl of alphabet cereal, Gonzo realizes that he may not be alone after all and that evening, he climbs to the rooftop of the Muppet boarding house to watch the sky.

Hoping to contact the aliens, Gonzo makes an impromptu appearance at the television studio for UFO Mania during a live broadcast, where Miss Piggy is working.

Unable to convince his friends of the aliens' existence, Gonzo is lured by Agent Barker to K. Edgar Singer of C.O.V.N.E.T., a top-secret national security facility whose mission is to investigate threats of extraterrestrial attacks.

Meanwhile, after Miss Piggy interrogates Barker, she, Kermit, Fozzie, Pepe, and Animal go to rescue Gonzo and Rizzo from C.O.V.N.E.T., using various inventions from Bunsen and Beaker.

Meanwhile, Rizzo escapes from medical research and frees Gonzo from the dissection table, while Singer and Luft witness the other rats attack the surgeon Dr. Phil Van Neuter.

As a result, his characters Miss Piggy, Fozzie Bear, Animal, and Sam Eagle were performed on set by other puppeteers, with Oz later dubbing his voice in post-production.

In addition, Muppet performer Kevin Clash was also unavailable for most of the shooting, due to scheduling conflicts with his work on Sesame Street (1969–present).

[8] When asked about his experience ten years after the film's release, co-writer Joseph Mazzarino revealed that he left the production before shooting started, due to changes made to his draft of the screenplay.

He stated that his draft included parodies of Men in Black, Contact (both 1997) and Alien (1979), and that Randal Kleiser had been selected to direct the film.

Some tracks were remade by contemporary artists, such as "Shining Star" by the Dust Brothers featuring Jeymes, and "Dazz" by G. Love and Special Sauce, recorded at Muscle Shoals Sound Studio in Sheffield, Alabama.

Gonzo's performer Dave Goelz had also recorded a new rendition of "I'm Going to Go Back There Someday" for this film, a song which had originally appeared in The Muppet Movie (1979).

[15] On October 26, 1999,[16] the film was released on VHS and DVD with supplemental features such as a blooper reel and an audio commentary by Kermit the Frog, Gonzo, Rizzo, and director Tim Hill.

[23] Roger Ebert of the Chicago Sun-Times gave the film a two-star rating (out of four) and concluded his review by saying that "maybe Muppets from Space is just not very good, and they'll make a comeback.

"[24] Conversely, Robin Rauzi of the Los Angeles Times gave the film a positive review, stating that "twenty years after The Muppet Movie and 30 after the beginning of Sesame Street, there is still life in these creations of felt, foam rubber and fake fur.

"[25] Michael Wilmington, reviewing for The Chicago Tribune, praised the puppeteers' performances, but remarked "[t]his picture isn't goofy or dreamy enough, however engaging it may be to re-encounter the intrigues of Miss Piggy, the wistfulness of Kermit or the weirdness of Gonzo.

"[26] Lawrence Van Gelder of The New York Times felt the "Frenetic movement and loud music overwhelm warmth and compassion, and the balance of character, plot, irreverent humor and innate decency that made some of the earlier Muppet movies so welcome is lost.