After the Consortium were stopped, and the de-activation of the Meta-Nanites, Rex faces a new threat, while Van Kleiss attempts to survive in outer space, after getting away from the evo cure event. Now the new villain, Zero, a long-time teacher who has history with Six, has sensed that Nanites are still reprogramming, meaning they still excist, as he plans to start something that will change him.
- Rex Salazar (Daryl Sabara) - Works on higher productions!
- Agent Six (Wally Kurth) - ???
- Bobo Haha (John DiMaggio) - ???
- Rebecca Holiday (Grey DeLisle) - ???
- Noah Nixon (Fred Savage) - ???
- White Knight (J.K. Simmons) - ???
- Beverly Holiday (Jennifer Stone) - seems to be love rivals with Circe
- Circe (Tara Sands) - Rex's new girfriend
- Caesar Salazar (Freddy Rodriguez) - now head of an scientific organization, known as Project N.A.N.I.T.E.S. (Short for National. Aliance. Natural. Independence. of Total. Extreme. Security)
- Peter Meechum (Will Wheaton) - ???
- Gabriel Rylaner (Brent Spiner) - ???
- Dr. Evan Moses (Peter Woodward) - the gray-haired scientist in Caesar's flashback in Ben 10/Generator Rex: Heroes United
- Annie (Danica McKellar) - ???
- Claire (Kath Soucie) - ???
- Jungle Cat (Kevin Michael Richardson) - ???
- Ben Tennyson (Yuri Lowenthal) - ???
- Gwen Tennyson (Ashley Johnson) - ???
- Kevin Levin (Greg Cipes) - ???
- Grandpa Max (Paul Eiding) - ???
- Zero (John DiMaggio) - the main antagonist, Six's mentor, and the head of the Six, plans to collect all nanites in order to change him, he has a hispanic accent
- Van Kleiss (Julian Sands) - Can't survive in space with out the soil
- The Pack: - ???
- Biowulf (Troy Baker) - ???
- Skalamander (John DiMaggio) - ???
- Breach (Hynden Walch) - ???
- Ibol (Arnold Vosloo) - plans to overthrow Van Kleiss
- Waspix (Charlie Adler)
- Van Kleiss' Apocalypse: - ???
- H20 (Maggie Blue O'Hara) - sadisfied water girl with nanites
- Volcano (Bumper Robinson) - flame black boy with nanites
- Porphyrion (Khary Payton) - big strong earth boy with nanites
- Pinnocio - (A.J. Buckley) - skinny rad wood boy with nanites
- Heavy Metal (Danny Cooksey) - juvenile abs metal boy with nanites
- Hunter Cain (Nick Chinlund) - now lost weight and looks more similar to the Young Justice version of Sportsmaster
- Alpha (Kevin Spacey, Daryl Sabara) - now became Negative Rex, after he has been fused with Rex's blood by Caesar
- Vilgax (Steven Blum)
- Consortium: - currenly locked up by the government
- Black Knight (Jennifer Hale) - revealed that behind her bang is a Scar on her face, and that she asked Van Kleiss if he knows who she is when it has been a very long time, it is revealed that she is also an Orochi Evo!
- Anthony Hayden-Scott (Robin Atkin Downes) - ???
- Roswell (Troy Baker) - ???
- Reddick (Robin Atkin Downes) - ???
- Xanubian - ???
- Crab E.V.O.
- Troll E.V.O.
- Cat E.V.O./ Dr. Holiday
- Arial E.V.O.