Dragon Ball has always had an interesting relationship with spin-off stories. Although they often go out of their way to be as massive or ambitious as possible, they often fail to ever have any impact on the actual core storyline. That carries over to characters like Android 21, a villain who has only appeared in a video game.
But is there a chance Dragon Ball FighterZ's villainous Android 21 could ever fit into the main Dragon Ball canon?
WHO IS ANDROID 21?
Android 21 is the primary antagonist of Dragon Ball FighterZ. The former wife of Doctor Gero, she's introduced with two possible origins: one is that she'd been adapted into an android, and the other is she's a bio-organism similar to Cell. Either way, she is revealed to be like similar to Cell, composed of the DNA of many of the greatest warriors in the universe. Android 21 rebuilds Android 16 and uses him to help claim the Namekian Dragon Balls for herself.
Using them, she's able to resurrect classic villains like Frieza, the Ginyu Force, and Cell. She also finds a way to take control of Androids and 17 and 18, as well as cloning the various Z-Warriors. She draws on the power from her Clones of the heroes, growing more and more powerful. It's eventually revealed that she wanted to resurrect all the villains so she could consume them and gain their power, making herself stronger. But she slowly loses control of herself, with her Buu-tendencies making her more destructive and giving her an insatiable desire to consume and absorb others.
IS ANDROID 21 CANON?
There's always been a question about how canonical the Dragon Ball spin-off stories are. Many of the older tie-in movies (which introduced popular characters like Cooler and Broly) have ultimately come to be considered non-canon, due to how they throw off the timeline and flow of events in the core one. In terms of the overall storyline, the events of Dragon Ball FighterZ could have potentially taken place in-between the events of the Universe 6 Arc and the Universal Survival Arc in Dragon Ball Super. This would account for the amount of power possessed by the heroes (notably Gohan, who'd achieved his Mystic Upgrade for the game).
The thing that complicates matters is that there are actually three plotlines in Dragon Ball FighterZ, each of which sees the battle against Android 21 play out differently from the various perspectives. This resulted in different events happening in each Saga. The Hero Warrior arc focuses on the Z-Warriors luring Android 21 to Supreme Kai's planet after she's restored (and consumed) all of the villains. The heroes work together to bring her down, ultimately creating a massive blast together to wipe her out.
The Enemy arc focuses more on the villains who'd been restored by Android 21 and Android 16. Android 21 is a more furious warrior and ends up destroying Android 16 for failing her. Ultimately the heroes and villains come together to help stop her. However, with villains now fully restored and united, the Z-Warriors find themselves confronted with their greatest enemies, more powerful than ever.
In the Android arc, the Androids (16, 17, 18 and 21) are more crucial to the story and afforded a surprising amount of depth. Android 21 and her character arc are especially explored, including her splitting into two versions of herself -- one good, one evil -- caused by Android 16 sacrificing himself to make her see the severity of her action. In this version of events, the good Android 21 eventually sacrifices herself to defeat her evil half by tackling her and allowing Goku's Spirit Bomb to destroy them both.
WHY IT DOESN'T WORK
Sadly, it's unlikely that Android 21 could make her way into the canon as she is now. She does appear in Dragon Ball: Kakarot in a cameo at Capsule Corp, finding a way to tie her to the greater storyline. The biggest hiccup is the return of Frieza, which is a major plot beat in the Dragon Ball Super "Tournament of Power" Saga. Frieza's return was a major moment with Beerus and the others in the buildup to that arc, so it undercuts that tension to have Frieza literally restored just before this. Her arrival in the core Dragon Ball universe could also risk lessening the power of Android 16's death if she restored him along the way just so he could sacrifice himself again.
And that's a shame! Android 21 is a visually engaging villain with a surprising amount of depth. While she has a similar "copy" trait to previous villains like Cell and Buu, she also has a level of intelligence and skill that separates her from the other villains in the franchise. Her connection with Android 16 and attempts to control her more Buu-descended half make her a more chaotic villain that actually has a conflict at her core. She's an interesting enemy for the heroes to confront and would be a fun villain to see make the leap into one of the future canon Dragon Ball stories (like with Broly as a result of the recent Dragon Ball Super: Broly film), but the creators would have to do some heavy lifting to figure out how to make it work.