Bart vs. the Space Mutants is a 2D side-scrolling platformer. In the single-player game, Bart Simpson is the only one who knows of the aliens' secret plan (thanks to his new x-ray glasses which he can see the aliens with) and he has to stop them from collecting the items they need to build their "ultimate weapon" to take over the world. There are a total of five levels, in which Bart must collect or destroy a certain number of these items (purple objects in the first level, hats in the second, balloons in the third, exit signs in the fourth, and nuclear rods in the fifth). If Bart loses a life he says "Eat my shorts man". Another objective of Bart vs. the Space Mutants is to help Bart convince the other members of the Simpson family about the aliens' existence so that they will help him during the levels.

In order to get to some of the items and progress through the game, Bart must use equipment such as rockets and cherry-bombs, which are bought with coins that can be collected by getting rid of aliens. Bart is controlled by the player both on foot and on a skateboard. To get rid of aliens, which are disguised as real humans, he needs to jump on their heads. The game increases in difficulty for every level, and Bart meets up with a boss at the end of the first four. The levels are familiar to fans of The Simpsons and some of the television humor appears in the game: for example, in the first level Bart can make a prank call to the bartender Moe in order for him to run outside so that the player can spray paint his purple apron (an example of an item that the aliens need) into a red color that the aliens do not want. The game also includes some minigames.

Bart vs. the Space Mutants was the first ever video game based on the animated television series The Simpsons, and includes the theme song from the show. The game was designed by Garry Kitchen. It was published in 1991 by Acclaim for the Nintendo Entertainment System, Sega Master System, Atari ST, Amiga, and ZX Spectrum, and by Ocean Software for the Commodore 64 and Amstrad CPC. The game was published in 1992 for Mega Drive/Genesis and the hand-held Game Gear console under Acclaim's Flying Edge label. A portable LCD toy of the game was also published by Acclaim in 1991.Imagineering developed Bart vs. the Space Mutants for the Nintendo Entertainment System, Atari ST, and Game Gear, while Arc Developments developed the game for the ZX Spectrum, Commodore 64, and Genesis.

According to the magazine Hispanic Engineer & Information Technology, the game was a best-seller. Reviews of Bart vs. the Space Mutants have been mixed. One of the authors of the book Video Game Bible: 1985-2002 called Bart vs. the Space Mutants "the best of the Simpsons titles on the NES." However, another contributor to the book said it "falls flat, mostly because it relies too much on its license [The Simpsons] and not enough on solid platform action." Many critics have described the game as difficult. An author for the Italian newspaper la Repubblica said the levels are not easy, and the Swedish edition of Sega Force described the game as both difficult and boring.Nintendo Power (which rated the NES game 66/100) wrote: "Bart Simpson has finally made it to the NES from Acclaim. His adventure, though, is anything but a game for underachievers. This game is very challenging and could be frustratingly so to some players. The tasks that you must perform to complete the adventure require patience and skill."

The NES version of Bart vs. the Space Mutants received a B rating from Lou Kesten of Entertainment Weekly, who noted that "the biggest drawback of this game is its brutally difficult opening section. However, what makes it challenging are clever strategic puzzles rather than thumb-bruising acrobatics. Bart tests reflexes and imagination in a way all too rarely seen in video games."The Video Game Critic's David Mrozek was more negative, giving it a D grade and noting that "the difficulty is insane!" He added that the game "is actually quite fun to play, but it's relentlessly unforgiving, requiring you to complete every single goal flawlessly! [...] Since there's no password, you're always doomed to repeat the early stages, and considering the difficulty, that oversight is unforgivable."

James Leach of Your Sinclair gave the ZX Spectrum game a 92/100 rating, writing that "I'm really into this game. As far as I can see, it's got everything it should have. It's fast, it's easy in places and dead wicked in others and it's got a massive amount of variety. What more could you want? [...] The graphics are very cartoony, as you'd expect, and there's pots of colour." Leach also noted that the idea of including minigames in Bart vs. the Space Mutants "is pretty inspired, and makes the game even more fun." A reviewer for Crash also gave the ZX Spectrum version a positive review, with a 91/100 rating. He praised the variety and gameplay of the game, and noted that "while it may sound pretty basic [...] it’s when you start discovering things, making use of objects, finding hidden treasures that it really comes alive. And achieving an objective is satisfying because the route to completion can be pretty tough (especially some of the platform elements)." The reviewer also noted that "if you’re a Simpsons’ fan the game’s incredibly appealing, the graphics all reflect Matt Groening’s cartoon very well. And how much of a fan you are dictates how much you’re really going to enjoy this [game]. Non-fans can still get loads of entertainment, but some parts may be frustrating if you’re not into the characters."

In 2009, 1UP.com editor Bob Mackey reviewed the NES game in 1UP.com's official Retro Gaming Blog. Although he liked the first level for "mixing an impressive amount of references from the show with gameplay that has a pinch of point-and-click adventure in", he expressed his dislike for the other levels: "Unfortunately, either due to lack of ideas or lack of time (most likely the latter), the rest of Bart Vs. the Space Mutants doesn't quite live up to the promise or ambition of the first level; the remaining four stages devolve into a frustrating and generic exercise in platforming that lacks all of the little references that made the beginning of the game somewhat authentic." Mackey described the game's controls as "terrible".