After the events of Crysis 2, Psycho and Prophet travel the world looking for the Alpha Ceph, the ultimate Ceph leader. Prophet and Psycho finally trace the Alpha Ceph in Russia and imprison it. However, shortly afterwards CELL Corporation, now attempting global domination of land and technology, disables Prophet in Siberia and captures all the Nanosuit soldiers, skinning them of their suits to recover the Ceph genetics stored in them. CELL transfers Prophet to a facility in New York, encased within a giant "Nanodome", to skin him. He is saved by a resistance force, led by Claire Fontanelli and Karl Ernst Rasch, as Prophet is the only Nanosuit holder left who can stop CELL. Psycho, who was saved by Claire after being skinned, explains to Prophet that during his absence, CELL used Ceph technology to generate unlimited energy, and gained a monopoly over the world's power supply. Those who could not pay for energy were enslaved by debt to CELL. The source of CELL's power generation for the entire world, called System X, is located in now abandoned New York. The resistance group wants System X destroyed to free the world from CELL.

After Psycho and Prophet disable System X's core, it turns out that it is a system protocol designed to contain the Alpha Ceph while draining energy off of the alien. However, the secondary defense protocol was initiated, causing the power facility to self-destruct. The Alpha Ceph, free from containment, opens a wormhole to the Ceph homeworld. They plan to send an even larger force to invade Earth through the wormhole and terraform it at the expense of all local life's extinction. With the Alpha Ceph no longer dormant, the Ceph coordinator reactivates, and a coordinated Ceph attack ensues.

After unlocking his potential ability by removing some neural blocks in his suit, Prophet learns that CELL plans to use Archangel, a satellite-based energy distribution device that can draw power from the world's power grid, as a directed energy weapon to destroy the Alpha Ceph. Firing it would cause a chain reaction that would destroy Earth. They shut off the weapon before it has enough energy to fire. Along the way, Psycho discovers Claire was one of the scientists who reluctantly skinned him, causing friction in his previously romantic relationship with her. Unfortunately, Karl, who had secretly used Ceph technology to extend his lifespan, is possessed by the Ceph and critically wounds Claire while psychically crippling Prophet. Regaining control after Psycho shot him, he sacrifices himself to distract the Alpha Ceph. Prophet, Psycho, and Claire board the VTOL and battles with Ceph ships, eventually crashing. Claire dies in the process. Psycho, saddened by her death, laments to Prophet that he is powerless because he no longer possesses a Nanosuit. Upon being told that his lack of a Nanosuit saved him from Karl's control earlier, Psycho, now going by his real name, Michael, finds another VTOL to take Prophet to the Ceph.

Michael and Prophet head towards the Alpha Ceph, but are bogged down by the Ceph Master Mind. Prophet finds his way through the Ceph Army hordes and kills the Alpha Ceph which in turn kills all other Ceph troopers in the area. However, they do not have enough time to destroy the Ceph wormhole structure and the beam powering the wormhole pulls Prophet into space. Now in orbit around Earth, Prophet sees a massive Ceph warship coming through the wormhole. Recalling Archangel's power, Prophet wakes up and hacks into the satellite, and uses it to destroy the warship. The explosion collapses the wormhole and Prophet is pushed back to Earth. He crashlands in the water near the Lingshan Islands where the events of Crysis took place 27 years earlier.

When Prophet wakes the next morning, he is in an abandoned hut in Lingshan. A television playing in the background informs him that CELL's assets were frozen by Senator Strickland as the corporation is under investigation. As the neural blocks are removed from the Nanosuit, the suit's outer layer is changed to reform Prophet's former physical body, resurrecting him. He walks out onto the beach and relinquishes his past by throwing his tags into the water. He then decides to use his actual name "Laurence Barnes" from then on. The game ends with Prophet walking back to the shed and activating his stealth ability. In a post-credit scene, two CELL soldiers are shot by Michael after they rushed three board members into a bunker. Michael later claimed that he would like to make a complaint to the board members regarding his treatment at one of their "hospitals".