Functioning as a classic 3D level-based beat 'em up, Spider-Man: Friend or Foe has Spider-Man and his allies enter world levels via the Helicarrier, which serves as the main hub. Players will primarily control Spider-Man, though they are able to switch to the sidekick accompanying him at any point during a level. A second player has the option to join in and play as the sidekick. Each character has their own unique combat style. New sidekicks are recruited as the story progresses, and may be either heroes or villains, the latter of whom need to be defeated in a boss battle first. The boss battles however only feature Spider-Man as the sole playable character and not the sidekick character.
Players can acquire tokens for upgrading combat abilities, power-ups that can temporarily enhance the player, and DNA Helix collectibles that unlock additional content, such as character bios and concept art. In addition, players can find secret rooms throughout the levels that, once cleared of enemies, will be unlocked for use in the two-player versus mode.
All characters can be upgraded via a technology tree. Spider-Man himself has the most extensive upgrades to his combat abilities, with three entirely separate interchangeable web modes that can be unlocked and utilized (web line, web shoot, and web stun). Each other character has one unlockable special move. Spider-Man and his allies can also perform Hero Strikes that wipe out entire waves of enemies. Each Hero Strike is different depending on the used ally, though the effect is the same. Hero Strikes can only be performed any spending tokens that can be found in the world or purchased from the upgrade store.