Gameplay features an energy system that limits the amount of mission-based combat a player can engage in. Energy is automatically recharged over time at a set rate, or players can replenish it manually. As players increase their level, the energy limit increases. Game items that affect the game (e.g. crystals) can be found at the end of a mission. In addition to the missions, users can also fight against opponents in the game's 'Versus' mode, which pits their champion against other players' champions in one-on-one matches or in a three-on-three limited time arena. Marvel Contest of Champions requires a constant internet connection in both single-player and multiplayer modes.

The controls are designed for touch, rather than tweaking buttons or virtual joysticks. Gameplay includes light, medium and heavy attack options, as well as blocking and dodging. Characters can back up or sprint forward, and each hero has his or her own three special attacks (unlocked through levels and stars), as well as unique abilities and signature powers. Synergy bonuses reward players for combining characters with unique relationships. For example, placing Dr. Doom and Mr. Fantastic on the same team rewards each team member with a 6% increase in attack power. When a character takes damage and deals damage, the power meter fills up, indicating the potential for unique moves. As players upgrade their characters, more powerful special attacks are possible, but they can be used less frequently because they cost more energy.

Characters can be upgraded with ISO-8 and gold, and upgraded with Catalyst, which are earned while fighting in story missions, special events and arenas. Profession-specific ISO-8s provide bonuses to heroes of a given profession. Completing missions provides XP (experience points) and unlocks the ability to add more heroes to a player's mission team, up to a maximum of 5 heroes. In addition to participating in the global chat feature, players can also join alliances. Alliances allow chat between other members and offer the opportunity to work together in alliance missions and wars, earning glory by upgrading materials and shards to form crystals.