Nickelodeon All-Star Brawl 2 has been noted as having almost zero similarities to the game it is a sequel to from a gameplay perspective. Gameplay and moveset designer and community manager Thaddeus Crews would address this disparity in a short Twitter thread shortly after the sequel's launch by reassuring fans who prefer the first NASB that the sequel was not intended as a replacement for the first game:

Originally, Donatello's Super Move was intended to be slightly different. Instead of driving the Turtle Van and shooting lasers at opponents with the other 3 Turtles, he would've perched atop the van alone, remote in hand, and rammed opponents directly.

In the Switch version of Nickelodeon All-Star Brawl 2, there exists a glitch where Rocko's winning animation will show a giant black texture in an unfortunate spot, resembling a vertical censor bar. This has a coincidental resemblance to a running gag from Rocko's Modern Life, where a horizontal censor bar will cover up Rocko's bottom half whenever he is shirtless, despite him usually being able to go pantsless without issue, being a cartoon animal. This has yet to be patched.

There are two attacks in the game that reference games developed by Ludosity, the studio who developed the first Nickelodeon All-Star Brawl game and also provided support on the second game. The Angry Beavers' jab attack is named after the platform fighting game Slap City, while Invader Zim's airborne back light attack is named after a Flash game developed in the company's early years called Garden Gnome Carnage.

Rocko's model in Nickelodeon All-Star Brawl depicts him with underwear underneath his Hawaiian shirt, something that is not true of his standard character design in Rocko's Modern Life. This change was reverted in Nickelodeon All-Star Brawl 2 to match his original design.

In Nickelodeon All-Star Brawl 2, Korra has three neutral specials selected based on the context of their use: a water projectile in the air, a non-offense based slippery puddle on ground, and a torrent of damaging water that goes up and down when used with Slime, regardless of location. This move was originally going to function like it contained three extra special moves in the place of one, where you could do another direction input after starting the move to choose a form (not unlike like Gerald's down special move in the final game). When the move was reworked due to its complexity, it was decided to "shuffle around the pieces" into something more easily understood to avoid wasting finished animations and props and having to make new animations close to the deadline.

In Garfield's alternate costume texture, there is a portion devoted to Garfello, Garfield's Ninja Turtle alter ego from the Garfield Meets the Teenage Mutant Ninja Turtles short comic published in the 1992 Teenage Mutant Ninja Turtles Magazine.

There is an unused model of the Statue of David by Michelangelo in Squidward's prop set. This was likely intended for his air down strong, where he slams down with a block of marble, referencing the SpongeBob episode "Artist Unknown", where SpongeBob makes the same statue by accident. The model has a clam on its groin as censorship, just like in the original episode, but does not have the nose Squidward places on it.

One of Garfield's voice lines in Nickelodeon All-Star Brawl 2 is "I'm sorry, Jon", a reference to an internet meme known as "Gorefield", where Garfield becomes an eldritch monster, and usually utters some variation of the line after or during his rampage.

Despite many of the more unusual character picks in the first Nickelodeon All-Star Brawl being noted as characters the development team had to push Nickelodeon into allowing them to use, Grandma Gertie in Nickelodeon All-Star Brawl 2 was actually pitched by Nickelodeon corporate, something community manager Thaddeus Crews has stated to be akin to "selling blood to a vampire".

Squidward's forward tilt in Nickelodeon All-Star Brawl 2 is based on a meme that went viral around the first game's pre-launch, showing a screenshot of Squidward kicking with poorly aligned fighting game hitboxes and the caption "AH HELL NAW SKODWERD GOT THE JANKY ASS HITBOX". Despite this origin, the move's hitbox "isn't very janky".

In the weeks prior to Nickelodeon All-Star Brawl 2's release, a near-complete prototype build of the game leaked online. The Twitter account for the game's main developer, Fair Play Labs, accidentally retweeted a GIF of SpongeBob dancing from an unrevealed sound test mode and promptly deleted it. Community manager Thaddeus Crews expressed that, while he didn't have a particular moral problem with fans playing the leaked build, he advised against competitive players using it for practice due to how outdated it is.

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

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.

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.

In the launch version of Nickelodeon All-Star Brawl 2, GIR's voice lines were not artificially pitched up as they were in the Invader Zim series, making it sound as if they had got a very poor replacement actor to those not familiar with how GIR's voice was originally made. GIR's voice actor Rosearik Rikki Simons pointed this out on Twitter, and it would be resolved in a latter update. However, the updated GIR voice lines still don't have the digitizer voice filter he had in the original series.

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 December 2023, information spread about Warner Bros. Discovery, which owns Cartoon Network among other major animation brands, potentially merging with Paramount Global, which owns CN's long-standing TV animation rival, Nickelodeon among other animation IPs. Although this deal would not come to fruition at the time, Nickelodeon All-Star Brawl game designer Thaddeus Crews commented that he would take the chance to work on a Cartoon Network vs. Nickelodeon fighting game "in a goddamn heartbeat".

Nickelodeon All-Star Brawl 2, like the first game, contains unused calls from the announcer. Interestingly, a good chunk of these voice calls are for characters who could be clones or otherwise have a similar body shape to playable fighters, such as DoodleBob, Dark Danny Phantom, Nermal, Abrasive SpongeBob, Squilliam Fancyson, and La Tigresa. Perhaps most interestingly, Lucy Loud's ghost ancestor, Lucille Loud, is the only The Loud House character with an unused announcer line, despite the show's protagonist Lincoln having been cut from the first NASB and the show being based on a large ensemble cast of sisters. Michelangelo and Leonardo are the only cut veterans from the first game with unused announcer voice clips. None of them are from new shows, with a technical exception in the form of the name "Tak", which most likely refers to the Invader Zim character, as she would fit a clone role being an Irken invader like Zim, but could also potentially be for the titular character from the Tak series, though this is unlikely given that the game series had effectively been abandoned by Nickelodeon following the cancellation of its animated series in 2009.

Strangely, before the unused voice lines were dumped and publically uploaded to the internet, an almost entirely accurate list circulated online with Goku from Dragon Ball listed as an announcer call, likely a meme-based in-joke regardless of if it is real or fake, a name which was not included when the voice calls got datamined proper.

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.