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Similar to the original, Rebirth is a top-down 2D roguelike game where the player controls the character Isaac (or 10 unlockable characters) as he adventures throughout his mother's basement, fighting off monsters and collecting power-ups.
Ultimately, the player aims to first defeat Isaac's mother while she tries to crush him underfoot, then moves inside her, where the player must defeat Isaac's mom's heart.
Rebirth is considered a roguelike-like game; the dungeon levels are procedurally generated into a number of rooms including at least one boss battle, and the game has permadeath: once the chosen character dies from taking too much damage, the game is over and the player will have to restart.
Rebirth allows the player to save the state of the game, allowing them to quit the game during a run, and come back later to finish that run, though this save state is deleted upon restarting the game.
The game is controlled similarly to a twin-stick shooter: the player moves their character around the screen while they are able to shoot the tears that they cry in another direction.
These tears act as bullets to defeat enemies that try to harm the player-character. The player-character's health is tracked by a number of hearts: the character can find items that can replenish hearts while others grant the character additional hearts, extending their health.