Abe's Oddysee is a two-dimensional side-scrolling platform game. The game is split into screens; when the player moves into the edge of the screen, the environment is replaced. Most screens include various puzzles which must be solved through the use of Abe's unique abilities: GameSpeak, possession, activation or deactivation of mines or levers, and rocks, grenades or meat chunks which can be picked up and used in a variety of situations. Normal abilities include creeping, walking, running, rolling, hoisting, jumping, slapping and crouching, all of which have specific application and make up a necessary arsenal of moves.

The game features no user interface or heads-up display. Information is conveyed to the player in a number of ways; through instructive screens which can be activated by the player character, through scrolling messages in the background, or through groups of fireflies which can arrange themselves to produce words should the player character chant near them. No characters in the game have hit points; instead, being attacked (such as being shot or mauled) causes instant death. However, the player has unlimited lives, and upon death will re-spawn at the beginning of the level.

While the focus of the gameplay is surmounting screens, there is a secondary focus on rescuing enslaved Mudokons. GameSpeak is a pivotal ability in this respect; at the press of a button, the player character will utter short phrases which can be used to control allied non-player characters - to pull extra levers, to follow the player character, to attack enemy characters in the current screen, or simply to "wait".

Possession is the player character's ability to take control of Sligs in the same screen by chanting. Possessing Sligs is a necessity in certain situations, usually to kill other enemy Sligs in the nearby screens or to give commands to nearby Slogs. However, when possessing a Slig, the player character remains immobile and vulnerable to attack. Upon abandoning control of a possessed Slig, the victim will explode.

Slave Mudokons are rescued through "Bird Portals". If the player character chants when in the same screen as a Bird Portal, and other Mudokons are nearby, the portal will activate and Mudokons will run through it, disappearing. Rescuing Mudokons is not crucial to playing the game; however, rescuing at least fifty is necessary to get the "good ending", and many secret areas revolve around rescuing one or two Mudokons in particularly complex situations.

The purpose-created game engine and artificial intelligence for Abe's Oddysee is called A.L.I.V.E. (Alive Lifeforms In a Virtual Environment), and has been acclaimed for its realistic encounters and intelligent enemies.