Unlike Mega Man Powered Up, Maverick Hunter X is a reboot to the X series that has many changes to the story that completely disconnect it to the original timeline. It was the intention of Keiji Inafune to completely redo the first six games of the Mega Man X series, but this project was discontinued due to poor sales of Maverick Hunter X.

These are some examples of the continuity with the rest of the series being ignored:

Dr. Cain discovered X many years ago (as opposed to months), and is artificially extending his life via mechanical support to oversee the Reploids. He also fears he does not have long to live. Towards the end of The Day of Sigma, a missile also destroys his home in Abel City - with him inside it (although it is left ambiguous as to whether Cain had actually died or not).

Vile's story, barring his flashback to Sigma's release of him from his cell, is merely considered a "what-if" scenario, as it conflicts with X's game. However, the line by Sigma to "retrieve Vile" seems to foreshadow his remodel in Mega Man X3.

Dr. Light's reasons for sealing X are completely different from the version previously established. In the original storyline, Dr. Light sealed X in a special capsule that would basically test his moral integrity, because it would be necessary to determine whether X would ultimately make the right decisions when he entered the world. However, in Maverick Hunter X, Dr. Light is already confident with X's moral integrity, but seals him up because he believes mankind is not ready for him just yet.

Sigma's personality is depicted quite differently than in other games. Here, he is obsessed with the evolution of Reploids (which somewhat reflects his attitude in Mega Man X8), and is fascinated with X's potential rather than truly wishing to overcome the humans. He even directly states to Vile he plans to go Maverick to test X's abilities and bring out his true power, and instructs Vile to help him incite rebellion to help achieve this. As such, he also seemed to have gone Maverick of his own free will, although his statement when releasing Vile that he "needed someone who could go Maverick of [his] own accord" in the opening to Vile Mode implies that this might not necessarily be the case.

On a similar note, his interactions with X before the final battle are slightly different from the original, where he had been expecting Zero to arrive and was slightly annoyed that he was about to face X instead before ultimately realizing upon Velguarder's defeat that Zero may have chosen X to fight Sigma for a reason, while in the remake he was shown to be genuinely expecting X to arrive and hoping he did in fact meet the qualifications to face him.