Different Nickelodeon protagonists from a range of series are likened into ball form, and the player is made to shoot the ball form of the character at its respective antagonist (or more properly, its "nemesis"). For example, Aang is made to be shot at Azula. There is no formal end to the game; it is over when the player misses his or her mark.
The center of the game's screen displays the cannon from which a protagonist is shot. The cannon spins at a fixed rate, and the player must use his or her skills to make the ball shoot at the correct corner of the screen at the perfect time to hit the matching antagonist. The protagonists are input to the cannon at random and include: Aang, Fanboy of Fanboy and Chum Chum, Otis of Back at the Barnyard, Private of The Penguins of Madagascar, SpongeBob SquarePants of his titular series, and Timmy Turner of The Fairly OddParents. Their enemies are Azula, Boogregard "Boog" Shlizett, Snotty Boy, Blowhole, Plankton, and Francis respectively.
Each corner of the screen has one antagonist, also produced at random. Depending on what character resides in the cannon, one antagonist is supposed to be hit by the protagonist in the cannon. Aang hits Azula, SpongeBob hits Plankton, Timmy hits Francis, and so on.
The antagonists in the corners are replaced with each level beaten. The character within the cannon is almost constantly changing with every shot. The player must be creative as the game progresses; different objects will appear to obstruct the cannonball's path to its target. However, the more a ball ricochets off walls and obstacles, the more points are earned if the ball makes it to its destination.
Based on the game's characters and objective, Know Your Nemesis is named for the player's necessity to recognize different Nickelodeon protagonists and antagonists and use this knowledge to his or her advantage.