A puzzle game similar to Tetris, Dr. Mario features Nintendo mascot Mario as a doctor. Gameplay consists of dropping two-sided vitamin capsules into an 8×16-block playing field populated by viruses of three colors (red, yellow and blue).
There are six types of capsules, differentiated by color: red-red, yellow-yellow, blue-blue, red-blue, red-yellow and blue-yellow. The player must rotate and position these capsules on top of and alongside the viruses and other capsules in an effort to eliminate the viruses. Both viruses and capsules are eliminated when four or more objects of corresponding color are placed in a row or column. A player completes a level by eliminating all viruses on the playing field. The game will end if any capsules obstruct the bottle's narrow neck at the top row of the field.
The player can start at any one of 21 distinct levels (0-20), with levels up to 40 accessible by those who can clear level 20. Levels are differentiated by virus counts, ranging from four at level 0 to 84 at levels 20 and higher. Above level 20, each level starts with 84 viruses, thus levels do not increase in difficulty past level 20. Much like Nintendo's version of Tetris, the player may choose a level of difficulty to start, along with the game's speed and a selection of background music. Three levels of speed can be chosen: low, medium and high. Choosing the low option will make the game's background dark green, choosing the medium option will make the game's background blue and choosing the high option will make the game's background gray. Two kinds of music can be chosen: Fever and Chill.
The Game Boy version of the game is nearly identical to its NES counterpart. In keeping with the technical limitations of the device, the game features a playfield measuring 8×15-blocks and viruses of black, white, and gray. In addition, levels increase in difficulty after level 20 and may be impossible. The Fever song was updated with a few extra musical notes and a slightly faster tempo.
Two player gameplay in either version consists of two side-by-side playfields that can be level-adjusted according to the strength of each player. The first player to win three games wins the match. The objective is to be the first to clear the viruses or to block the opponent's field to the top.
An added element is the ability to "rain" down blocks into the opponent's playfield by clearing two, three, or four separate lines with a single vitamin (intentional branches of vitamin drops which exceed four lines cleared will be disregarded). An alternative method to raining four blocks is to clear four separate lines with two vitamins within the time between your opponents' current vitamin and his next vitamin (two quick double-line clearances, in other words).
The colors of pills rained down upon the opponent correlates to the colors of the lines cleared. Again, a clearance of more than four lines in this respect will be disregarded.