Several years after a devastating cataclysm known as the Second Impact, the remains of civilization are under attack by gigantic, misshapen beings only known as 'Angels', believed to be able to cause a Third Impact if they reach a certain destination. To fend them off, humans have created the equally massive, humanoid Evangelion Units, which can only have as pilots young teenagers able to fully synchronize with them. This is their story.
- Kodi Smit McPhee as Sheen G. Carrey, a troubled teenager who is naturally able to pilot an Evangelion Unit, and is therefore summoned to the city under Angel attack by his father.
- Stefanie Scott as Raye A / Raye B / Raye C, a quiet girl who is also a pilot and who always appears to return in one piece after withstanding seemingly lethal attacks.
- Haley Ramm as S. A. Langley, another child selected as a pilot who is brought in from abroad after the battles have already started. S. A. Langley is then revealed to be a beautiful red-haired girl with an equally fiery temperament.
- Dermot Mulroney as Kent I. Carrey, the father of Sheen G. Carrey and the director of NERVE, the powerful organization tasked with stopping the Angels and whose headquarters consist of a fortress guarding the monsters' goal.
- Liv Tyler as Miss Sutton, who remotely coordinates the pilots' actions, and also doubles as the teens' guardian.
- Rosamund Pike as Dr. Ritz-Zucco, a NERVE scientist who is one of the few aware of the true nature of the Angel-Evangelion conflict.
- Ian Somerhalder as Rio G. Kaye, an agent whose allegiance is not entirely clear. Rio G. Kaye and Miss Sutton share an on-again, off-again relationship.
- Austin Abrams as Ken Nyder, Sheen G. Carrey's classmate who is a fan of popular culture and who dreams of piloting an Evangelion Unit like his friend, unaware that he also holds the potential.