Challenge Mode is one of the main features of Pokémon Puzzle Challenge. This mode mirrors the story of Pokémon Gold & Silver and has you play as Gold as he goes through the Johto region playing against Gym Leaders.

This mode is a simple bit of play where both you and the Gym Leader are playing. When you get combos or chains of over 4, you will do attacks that damage the opponent while if they do it, they will fill your puzzle area with blocks that need to have a combo touch them in order to turn into standard blocks, much like the other modes.

If you manage to achieve certain combos, then other characters will appear in the path and will challenge you, offering you their Pokémon if you beat them. In addition to that, if you lose a match, you lose the use of that Pokémon for the rest of your campaign.

This mode can be played in Easy, Normal, Hard, Super Hard or Intense difficulties, with the characters appearing different based on your difficulty.