Dr. Mario is a falling block tile-matching video game, in which Mario assumes the role of a doctor, dropping two-colored medical capsules into a medicine bottle representing the playing field. This area is populated by viruses of three colors: red, yellow, and blue. In a manner and style considered similar to Tetris, the player manipulates each capsule as it falls, moving it left or right and rotating it such that it is positioned alongside the viruses and any existing capsules. When four or more capsule halves or viruses of matching color are aligned in vertical or horizontal configurations, they are removed from play. The main objective is to complete levels, which is accomplished by eliminating all viruses from the playing field. A game over occurs if capsules fill up the playing field in a way that obstructs the bottle's narrow neck.
Players can select the degree of starting difficulty any time a new game is started. The initial level chosen is a value between zero and twenty that determines the number of viruses to clear, and the three game speed options change how fast the capsules fall in the bottle. The player's score is based solely on the elimination of viruses, not on the time taken to complete the level or the number of capsules used. If players complete the highest difficulty level, they can continue playing to accumulate a higher score, but the number of viruses to clear remains the same. Additional points are awarded when multiple viruses are eliminated at once, but no additional points are awarded for initiating chain reactions, in which the elimination of one set of objects triggers the elimination of another set. The game speed is also a factor in how the game calculates scoring; higher speed levels yield more points.