The game is a much like multiplayer Tetris in previous entries in the series. The player tries to stack up tetriminos to create combos. These combos generate garbage blocks for an opposing player. When receiving garbage blocks, some can be prevented by performing their own combos. The game is played battle royale-style with the players being ranked at the end by where they placed. The other players' games can be seen beside the game space with a special mark if they were knocked out by the player. The player can only send their garbage blocks to one player and this is determined by using the right to select either Random, Badges (level), Killshots (those close to losing) or Counter (someone who is targeting the player). The better placement results in more experience to raise the player's badge level.
Tetris 99 has several themes, mostly based upon other Nintendo properties. These themes include a version based upon Tetris for the Game Boy, a Splatoon 2 theme, and a Fire Emblem: Three Houses theme. These themes are unlocked in events, where players must earn 100 points to obtain the theme.