Mickey's Safari In Letterland chronicles Mickey Mouse's globetrotting adventures (on a slightly modified globe) to capture letters for educational purposes. Goofy assists with chauffeur and data processing duties. Mickey can venture into any of the following 6 territories: Yukon, Swamp, Forest, Jungle, Pyramid, and Caribbean. In each area, his mission is to collect three diamonds that contain letters. Doing so will spell a word. Then, Mickey ventures to the end of the level and collects a large slab. If Mickey collects the three diamonds in the stage to spell a 3-letter word, Mickey spells the word with digitized audio samples and says the word, complete with an illustration. Then, the slab that Mickey collected at the end of the stage is fed by Goofy through a large machine that spits out a letter. It is up to the player to identify which letter this is.

This game is oriented towards very young children. As such, it is essentially impossible to fail. There are many enemies in the game but none actually inflict harm. Snakes, porcupines, hippos, alligators, and even baby seals-- Mickey just bounces off each. Mickey can also swim handily and sustain long falls.

Further, the game allows the player to point at letters on a board and have Mickey say them using the cartridge's library of digitized mouse voice samples.