At the start of the game, players only have access to Chikorita, Cyndaquil, and Totodile, but can unlock six more Pokémon by completing specific objectives in Challenge mode then defeating their trainer. Players can choose between different Pokémon that appear as part of the user interface. The game is heavily themed after Pokémon Gold and Silver, featuring characters and remixed music from those games. Using a Game Link Cable, two players can compete in standard versus play, Time Zone, or Line Clear. Garbage is an infinite mode similar to Marathon, but with increased difficulty due to garbage blocks frequently appearing on the grid. Puzzle involves clearing specific arrangements of blocks using a limited number of moves. Line Clear is a stage-based mode in which players must clear a certain number of lines to advance. Time Zone challenges players to achieve the highest score within a time limit.

Challenge is a competitive mode that pits the player against several computer-controlled opponents, framed as the player traveling around the Johto region challenging other Pokémon trainers and gym leaders. Marathon involves playing infinitely until the grid is filled and the player loses. The game features six primary modes of play. Concessions are made due to the game's limited screen size: Puzzle Challenge features a puzzle grid size of only 6x9 blocks, compared to the 6x12 grids of other Puzzle League games, and the opponent's grid is not visible, with a small meter instead indicating how close they are to losing. In competitive modes, players can perform combos and/or chain clears to cause objects called garbage blocks to fall on their opponent's grid, further filling it in an attempt to cause them to lose. A game typically ends when the blocks reach the top of the grid, at which point the player loses. Players can also perform combos by clearing more than three blocks at once, as well as chains when falling blocks from one clear cause another set of blocks to clear. Placing three blocks of the same color in a horizontal or vertical line will cause them to disappear. The objective is to remove blocks from the player's puzzle grid as new ones appear from the bottom. Pokémon Puzzle Challenge features gameplay similar to other games in the Puzzle League series players control a two square long cursor that can swap or move blocks around the field.

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