The show, X-Men: Evolution has a soft reboot, placing it in the same universe as Ultimate Spider-Man, Avengers Assemble, Hulk and the Agents of S.M.A.S.H. and Guardians of the Galaxy.
The X-Men have broken up, but find themselves reunited when Magneto threatens humanity again, as well as the Mutant Twins, Quicksilver and Scarlet Witch.
The X-Men find themselves confronting the MRD (Mutant Reverse Division) and Mr. Sinister, while unaware that an ancient threat called, Apocalypse is luring mutants to his side.
The X-Men are popular, despite Professor X's growing ego putting them at risk, while finding themselves at odds with a mysterious enemy, Jean's unknown power awakens a new dormant personality, while Cyclops discovers his father's existance, and Shadowcat meets the Guardians of the Galaxy.
The X-Men discover a dark and grim future where Sentinels ruled the world, and that Bolivar Trask is the catalyst of this future, creating Master Mold, and from the future, Nimrod.
- Charles Xavier/Professor X (Dwight Schultz, sounding similar to David Kaye) - his raise in tuition had outraged students, causing them to lose faith in the Institute.
- James Howlett Logan/Wolverine (Steve Blum) - the same Wolverine from Ultimate Spider-Man and Hulk and the Agents of S.M.A.S.H.
- Ororo Munroe/Storm (Cherise Booth, sounding similar to Kristen Williamson) - was accused of making a snowstorm in July, causing her to return to Wakanda and become T'Challa's queen.
- Scott Summers/Cyclops (Rino Romano, sounding similar to Kirby Morrow) - had been promoting a new line of sunglasses
- Jean Grey/Phoenix (Colleen O'Shaugnesy, sounding similar to Venus Terzo) - was the greatest foe the team dealt with, before returning to the X-Men, gains the Phoenix ego in Season 3
- Rogue (Ashley Johnson, sounding similar to Meghan Black) - had put the Mayor in hospitalization after shaking his hand without a glove, causing her to be quarantined.
- Kitty Pryde (Natalie Lander, sounding similar to Maggie Blue O'Hara) - had been doing a life as an actress when starring in a "Twilight" parody movie
- Kurt Wagner/Nightcrawler (James Sie, sounding similar to Brad Swalie) - was in the Circus before returning to the X-Men
- Hank McCoy/Beast (Neil Kaplan, sounding similar to Michael Kopsa) - had been running a new line of men's haircare products
- Jubilation Lee/Jubilee (Laura Bailey, sounding similar to Chiara Zanni) - had been doing a music career, she replaces Spyke as one of the returning X-Men: Evolution characters due to him being a hated character
- Allison Brie/Dazzler (Miley Cyrus) - her new album platinum released
- Caliban (Tom Kenny) - had been spotted as a monster in the sewers
- X-Force: assembled by Cable and Deadpool in Season 2 to help fight Apocalypse
- Nathan Summers/Cable (???) - his appearance is based on his appearance in Deadpool 2
- Wade Wilson/Deadpool (Will Friedle)
- Neena Thurman/Domino (???) - her appearance is based on her appearance in Deadpool 2
- Jesse Aaronson/Bedlam (Terry Crews) - his appearance is based on his appearance in Deadpool 2
- Gaveedra-Seven/Shatterstar (???) - his appearance is based on his appearance in Deadpool 2
- Axel Cluney/Zeitgeist (???) - his appearance is based on his appearance in Deadpool 2
- Peter W. (???) - his appearance is based on his appearance in Deadpool 2
- Telford Porter/Vanisher (???) - his appearance is based on his appearance in Deadpool 2
- Avengers: it was revealed in the Original Sins storyline that during the events of Avengers Assemble, "Night of the Avenged". That there was a compromise in the Avengers files.
- Tony Stark/Iron Man (Mick Wingert)
- Steve Rogers/Captain America (Roger Craig Smith)
- Thor (Travis Willingham)
- Natasha Romanoff/Black Widow (Laura Bailey)
- T'Challa/Black Panther (James Mathis III)
- Shuri (Daisy Lightfoot) - T'Challa's genius sister
- Kamala Khan/Ms. Marvel (Kathreen Khavari)
- West Coast Avengers: run by Hawkeye as team leader
- Clint Barton/Hawkeye (Troy Baker) - leads the group after leaving the Avengers, becomes a father figure and friend to Wanda by relating his criminal past with the Circus of Crime with her relation to Magneto
- Scott Lang/Ant-Man (Josh Keaton)
- Hope Van Dyne/Wasp (Kari Wahlgren)
- Vision (David Kaye) - gains romantic feelings for Wanda
- Wanda Maximoff/Scarlet Witch (Ashley Tisdale, sounding similar to Kelly Sheridan) - she has the same appearance as her MCU counterpart
- Pietro Maximoff/Quicksilver (Peter MacNicol, sounding similar to Richard Ian Cox) - he has the same appearance as his MCU counterpart
- Peter Parker/Spider-Man (Drake Bell) - it was revealed in the Original Sins storyline that he was a clone created by Dr. Miles Warren.
- Matt Murdock/Daredevil (Jason O'Mara) - has the same appearance as his MCU character
- Luke Cage/Power Man (Ogie Banks) - it was revealed in the Original Sins storyline that he left to gain money and used the heroes for hire to make a living.
- Danny Rand/Iron Fist (Greg Cipes) - it was revealed in the Original Sins storyline that he followed Luke into the business.
- Jessica Jones (Grey Griffin) - has the same appearance as her MCU character
- Ava Ayala/White Tiger (Caitlyn Taylor Love) - it was revealed in the Original Sins storyline that She went solo, but is taking dates with Peter, she realized that the supporting cast in Ultimate Spider-Man were actors to fool the clone.
- S.M.A.S.H.: it was revealed in the Original Sins storyline that during the events of Hulk and the Agents of S.M.A.S.H., that The Skrulls infiltrated the system.
- Bruce Banner/Hulk (Kevin Shinick for Bruce Banner, Fred Tatsciore for Hulk)
- Rick Jones/A-Bomb (Seth Green)
- Jennifer Walters/She-Hulk (Eliza Dushku)
- Thunderbolt Ross/Red Hulk (John DeLancie)
- Skaar (Benjamin Diskin)
- Guardians of the Galaxy: it was revealed in the Original Sins storyline that during the events of Guardians of the Galaxy, they got sucked into the D'Brys
- Peter Quill/Star-Lord (Will Friedle) - attracted to Kitty Pryde
- Gamora (Vanessa Marshall)
- Drax the Destroyer (David Sobolov)
- Groot (Kevin Michael Richardson)
- Rocket (Trevor Devall)
- Sam Alexander/Nova (Logan Miller) - it was revealed in the Original Sins storyline that he joined the group to earn his keep.
- Nick Fury (Chi McBride) - revealed to be the son of the original Nick Fury, it was revealed in the Original Sins storyline that He was a former Zodiac Agent.
- Team Coulson:
- Phil Coulson (Clark Gregg)
- Melinda May (Ming-Na Wen)
- Daisy Johnson/Quake (Chloe Bennet)
- Leo Fitz (Iain de Caestecker)
- Jemma Simmons (Elizabeth Henstridge)
- Michael Peterson/Deathlok (J. August Richards)
- Bobbi Morse/Mockingbird (Adrianne Palicki)
- Nick Fury/Man on the Wall (Jim Byrnes) - the original Nick Fury who uses LMD's in his place, appears in a storyline called, "Original Sin" in Season 3
- Erik Lehnsherr/Magneto (Ron Perlman, sounding similar to Christopher Judge) - the main antagonist of Season 1, his goal is to reconcile with his Children while trying to exact his revenge on man, his conflict with his children, Wanda and Pietro are the main focus
- En Sabah Nur/Apocalypse (Kevin Michael Richardson) - the main antagonist of Season 2, his goal is to destroy the world and rebuild it in his own image.
- The Inner Circle Club:
- Sebastian Shaw (Maurice LaMarche, sounding similar to Kevin Bacon) - the main antagonist of Season 3, the leader of Inner Circle Club, his goal is to finish what Mastermind started.
- Emma Frost (Claudia Black) - Shaw's right-hand
- Janos Quested/Riptide (Carlos Alazraqui)
- Azazel (Keith Szrabajka) - Nightcrawler's biological father
- Angel Salvatore (Kimberly Brooks)
- Jean Grey/Dark Phoenix (Colleen O'Shauganessy)
- Bastion (Roger L. Jason) - the main antagonist of Season 4, a fusion of Nimrod and Master Mold, his goal is to make the world free for machines.
- This show is set in the same universe as Ultimate Spider-Man, Avengers Assemble, Hulk and the Agents of S.M.A.S.H. and Guardians of the Galaxy, it turned X-Men Evolution into a soft reboot.
- The Original Sin storyline reveals some secrets from the deceased Uatu the Watcher:
- The show revealed ???
- Ultimate Spider-Man: ???
- Avengers Assemble: ???
- Hulk and the Agents of S.M.A.S.H.: ???
- Guardians of the Galaxy: ???