The player controls Luigi, who must travel around the world to find and return stolen treasures as part of a quest to locate his brother, Mario, who has been captured by Bowser.

[1] In the game, Bowser, king of the Koopas, has relocated from the Mushroom Kingdom to the real world where he has set up his headquarters in an Antarctic castle.

[2][1] Bowser plans to steal the Earth's treasures with the use of the Passcode-Operated Remote Transportation and Larceny System (PORTALS) which allows his Koopas to teleport anywhere in the world.

[2] The player has access to a computer which keeps track of various clues learned throughout the game, including information gained from speaking to people in the cities Luigi visits and pamphlets regarding the landmarks that have had something stolen from them.

Each city contains multiple tourist information centers as well as three stolen treasures, which are obtained by dispatching the Koopa who is carrying each one.

[2][1] In the version for Macintosh PC and MS-DOS, the number of treasures which have to be retrieved from the Koopas in each city varies, ranging between three and five that need to be recovered and returned.

[6][7] The player must summon Yoshi to Luigi's current location so the dinosaur can eat a Pokey that is blocking the level exit leading back to Bowser's castle.

[2][8][1] After helping five cities recover their missing artifacts, Luigi faces one of Bowser's Koopaling kids blocking the way up to the next floor.

[10][11] Its lead designer was Donald W. Laabs, who saw working with Nintendo as a way to compete with Carmen Sandiego creator Broderbund and hoped to license Mario for that purpose.

[12] In the United States, The Software Toolworks released a Macintosh version on CD-ROM and floppy disks in June 1994 under the title Mario Is Missing!

The new version included 127 QuickTime clips featuring 99 landmarks, like the Golden Gate Bridge and the Great Wall of China.

[6] GamePro, reviewing the SNES version, called the game "a good way to learn geography" but wrote that players should not expect it to be exciting.

[24] Nintendo Magazine System UK reviewed the SNES version and wrote that it succeeded as both an educational and entertaining game, while noting it would only be suitable for people of a certain age.

[15] Chris Cavanaugh of AllGame reviewed the SNES version and considered it to be "somewhat enjoyable" for children, but believed that adult players would not be interested.

Cavanaugh noted the colorful graphics yet criticizing the repetitive gameplay and the "virtually identical" appearances of each city.

He opined that the backlash against Mario Is Missing comes down to measured expectations; what is suitable or primally engaging at a young age could be dull and tedious at another.

[25] In 2016, Samuel Roberts of PC Gamer noted the computer version had poor pixel art and that every street has the same buildings on it, and all the NPCs are the same regardless where the players are going.