In Nickelodeon All-Star Brawl 2, Azula is voiced by Suzie Young instead of her original voice actress, Grey DeLisle - despite this, DeLisle returned to voice Frida Suárez in the same game.

During the prerelease of Nickelodeon All-Star Brawl 2, a set of placeholder pages were found on the game's website relating to different characters. Most notable of these pages was one for Helga, a character who was in the first Nickelodeon All-Star Brawl and hadn't been seen in All-Star Brawl 2 marketing materials or leaks at that point - this led a lot of fans to believe that Helga would be returning. Ultimately, she would only be a background cameo on the Aquarium stage.

Reptar's ice-skating attack resembles Bowser's dash animation from Super Smash Bros. Melee and Super Smash Bros. Brawl.

While most other characters in Nickelodeon All-Star Brawl 2 recieved revamped movesets, Jenny's moveset is nigh identical to her moveset from the first NASB aside from inputs that didn't exist in the NASB 1 moveset template. This is due to moveset and gameplay designer Thaddeus Crews considering Jenny's moveset to be one of his favorite kits from the first game.

In the reveal trailer for Nickelodeon All-Star Brawl 2, a set of gameplay footage from the first installment is shown. This is notable for two reasons, one being that the footage shows off multiple characters not featured in the second game, and that one scene shows a beta version of the Wild Waterfall stage with a smaller waterfall and different colors for the Thornberrys' ComVee. This would lead to a theory that the Wild Waterfall footage was taken from NASB 2 and accidentally inserted into the NASB 1 section of the trailer, which if true would confirm that Lincoln Loud and Leonardo were returning.

This theory was quite easily debunked by Lincoln and Leonardo using their models from the first game while everyone else got revised models, and a KO explosion effect featured in the snippet being different from one shown later in the trailer. Nigel Thornberry's character showcase would later show off a new Wild Thornberrys stage in place of Wild Waterfall, which was shortly followed by a leak showing Lincoln as an NPC cameo on the Loud Castle stage.

It has been implied that Garfield's neutral special in Nickelodeon All-Star Brawl 2 (where he transforms into the original, fatter 1970s version of the character) was originally going to feature him smoking a pipe, in reference to an internet meme based on a 1978 Garfield comic, where the last panel of a different Garfield comic is replaced with a panel of Garfield smoking a pipe with the same design. It is unknown if this was removed by the developers' choice, at the request of Nickelodeon, or at the request of the ratings board, but either way it was likely done to make the game more appropriate for its age demographic.

Many Nickelodeon fans noticed a significant omission of characters from the series The Fairly OddParents in Nickelodeon crossovers starting in 2008's SpongeBob SquarePants featuring Nicktoons: Globs of Doom, which was the final installment in the Nicktoons Unite! series where Fairly OddParents protagonist Timmy Turner had previously been part of the main ensemble cast. The reasoning for this is believed to be due to Nelvana, a Canadian distributor of children's content, holding the international licensing rights and copyright for the first 5 seasons of the show outside of the US, having used this to syndicate the cartoon on the rivaling Disney Channel.

Timmy Turner did later appear in the 2022 Apple Arcade game Nickelodeon Extreme Tennis. In response to a tweet speculating that this could lead to Fairly OddParents content appearing in Nickelodeon All-Star Brawl, the community manager for the latter game Thaddeus Crews posted a "heads-in-the-clouds" emoji. A playtester for Nickelodeon All-Star Brawl 2 alleged that the legal issues with The Fairly OddParents are so complicated and strung-out that a former Nickelodeon or Nelvana employee was gifted the copyright to Timmy Turner's pink hat design as a farewell gift.