According to Clover Studio's president and God Hand's producer Atsushi Inaba, the game was originally going to focus on "hardcore action" with little to no humor. However, after showing a trailer for the game at the 2006 Electronic Entertainment Expo (E3) which contained some comic relief, the team decided to integrate a large amount of comedy into the game based on the viewers' reactions. Mr. Inaba stated:

Due to the Genesis' inferior hardware compared to the CPS1 arcade board, many of the destructible items in the background are now indestructible. Additionally many NPCs are missing, such as the white dog in the first level.

Bone Crusher, the third boss of the game, has three attacks, one where he uses his flamethrower, one where he launches multiple missiles, and another where he rushes into the player. In the Genesis version he just rushes into the player and uses missiles; the flamethrower attack is missing.

There's a short cutscene that plays after the player defeats Scully, the first boss of the game, where Punisher interrogates Scully to find out about Kingpin's location, and once he's done he disposes of Scully. In the Arcade version Punisher kills Scully, while in the Genesis version he just tosses him to the side.

Nick Fury smokes a cigarette in the arcade version, with the cigarette being part of his character select portrait and his in-game sprites. In the Genesis version, he doesn't smoke, with the cigarette being completely removed.

The game's final boss Kingpin smokes a cigarette before the final battle. In the Genesis version he doesn't smoke.

The female ninjas' outfit shows more skin in the arcade version, whereas in the Genesis version they are covered up.

According to former Senior Vice-President of Capcom USA Christian Svensson, the reason why Cyclops, a mainstain of the series, is not in this game is because the team felt they already had too many X-Men characters and didn't want to add another one.

Gene from God Hand and Mega Man were in the final pool for possible playable characters, but neither of them made the final cut, because the team wanted to put other characters from the same category instead.

In the Country Life expansion, there is a decoration called "Jerry's Reeds" with the following item description:


This item is referencing The Last of Us Part II, specifically the character of Jerry Anderson, the leader of the group of doctors called the Fireflies who were attempting to create a cure for the Cordyceps brain infection at St. Mary's Hospital.

If Little Mac is KO’d by a practice fighter, the game will softlock.

If Lynn gets defeated during the tutorial fight, her victory cutscene will play despite her defeat. The “Enemy Phase” sign will then play on loop, essentially soft locking the game.

If Bowser defeats Mario at the very start of the game, it will soft lock as the developers never intended for Mario to lose.

In 2022, a pair of previously unknown cheat codes for the SNES version were discovered, presumably having been used for debug purposes:

•From the title screen, by holding the R and Y buttons on a second controller, and then pressing Start or A on the first controller, a new menu will appear showing Little Mac versus head profiles of all 16 fighters in the game, allowing you to select whoever you want for a one-off match. After the match is finished, you are sent back to the same menu.

•Also on this menu, an unbalanced two player-mode can be accessed if the second player holds down B or Y on their selected opponent until the match starts. As the opponent, using A, B, X, or Y in tandem with Up and Down will allow you to pull off every basic and advanced attack in each boss's arsenal. This mode is unbalanced in that every boss is still more powerful than Little Mac and have pauses with "tells" for when they are about to attack, and if dodged successfully will leave them vulnerable to attacks.

Due to the complex maze-like structure of Yoshi Valley, the HUD’s mugshot are reduced to question marks, and the player’s position in the race doesn’t appear at all.

This error would be eventually mostly fixed in Mario Kart 8, nearly 20 years after its debut. Some items like the Red and Blue Shells, occasionally, may miss the character in front of the player.

A fan mod for the game which allowed players to have sex with the character Johnny Silverhand, played by actor Keanu Reeves, was taken down at the request of the game's developer CD Projekt Red as they considered it to be potentially harmful towards those who had lent their likeness.

Despite this, at a promotion for the film The Matrix Awakens, when Reeves was told about it by the Verge, he expressed his pleasure for it.

Exclusive to the Japanese console version of the game are four multiplayer skins based off Yakuza characters Kazuma Kiryu, Shun Akiyama, Ryuji Goda, and Goro Majima.

Inside the Software Excess store in the Galaxy Galleria mall, if you click the Taste icon and then click a small dark rectangle in the top-right corner of the screen, a shopper will come running out from the right, being chased and shot at by a floating Sequel Policeman. This Easter egg went overlooked and undiscovered until 2021.

On the opposite side of the screen however, if you click the Smell icon and click the rectangle on that side of the screen, the narrator would say "Ah! Yeaaa!". Afterwards, if you turn your back on the clerk in the store, he will eventually give you the middle finger and laugh. This secret had been known before.

These Easter eggs were removed from the CD-ROM version of the game, even having gone so far as to remove the pixels of the middle finger from the clerk's sprite. However, they are still present in the EGA 16 and Amiga versions of the game that are based on the original disk version.

On Little States, in "Florida" near the rocket launch pad, there is a hangar that can be entered most easily with the Rocket Belt. When you enter it and then turn around, you will be warped to the hangar in "Seattle".

On Little States, near the rocket launch pad in "Florida", there is a small gas station. If you land any vehicle that needs fuel to run, your fuel tank will be automatically refilled.