LEGO Pirates of the Caribbean: The Video Game for Nintendo DS is similar to the console game, but features simpler graphics, fewer and smaller levels with their own level and puzzle design, and a unique dueling mechanic.

As in the console game, the handheld version allows players to play through events of the four Pirates of the Caribbean films, with the game released as a tie-in with On Stranger Tides. Cutscenes from the console version are partly reused, partly newly done to fit in with the different design. The handheld version features only four levels per movie compared to the console's five.

Actual gameplay follows the standard template of earlier LEGO games: players move through the levels playing as several characters with different abilities, whose skills must be combined in order to defeat enemies and solve puzzles. Collecting LEGO studs, bricks and other items like medallions and rum bottles allows the unlocking of bonuses. A unique feature of the handheld version are pirate duels: when prompted, players have to press a button rapidly, which is then followed by a quick-time event, for which two out of three of the indicated buttons must be hit for a successful strike against the enemy.