LEGO Indiana Jones 2 for handheld platforms is similar in gameplay to the game on consoles, but has simpler graphics and completely different levels. Unlike the console game, the handheld version focuses on the fourth Indiana Jones movie, with elements from the earlier films only appearing in mini-game format and some unlockable bonuses.

The story of Kingdom of the Crystal Skull is retold in three acts of four chapters each, with comic-book-style cutscenes between levels. The levels themselves follow the usual LEGO game format: players control several characters and can switch between them at will. Different characters have different abilities which must be used in combination to overcome challenges and solve puzzles. For instance, Indy can use his whip, Marion and other female characters can cross special ledges and Indy's son Mutt can use his knife to cut ropes and can also climb walls. A major part of the game is the collecting of LEGO studs, red and gold bricks and other hidden items, which unlock various bonuses like additional characters. Finding pages of Indy's journal unlocks one of 16 mini-games.

The mini-games are inspired by certain scenes from all four movies, including the rolling boulder run from Raiders of the Lost Ark, the mine cart chase from Temple of Doom and the three trials from Last Crusade. The games usually task the player to survive for a certain time or to collect a certain number of studs before dying or reaching the end of the level.