The game's producer Yoshinori Ono has stated in some interviews that the reason behind including Bad Box Art Mega Man and his highly exaggerated appearance, instead of any other version of the character, was due to Mega Man's co-designer Keiji Inafune's wishes. Ono said that when he asked Mr. Inafune about including the character in the game, Inafune responded with "No, that's not interesting, nothing interesting about that. We have seen Mega Man in fighting games before" and then asked Ono to give him "something original". Ono then decided to use the Mega Man from the "awful" North American box art from the first Mega Man game and "make it even wackier" by presuming that Bad Box Art Mega Man has aged since his picture was taken and used in the US box art 25 years ago. Ono said that Inafune "loved the idea" and that was what lead to his inclusion.

According to the game's producer Yoshinori Ono, the team considered putting Master Chief from Halo or Marcus Fenix from Gears of War as guest characters for the Xbox 360 version but they couldn't be added in the end. He stated:

According to the PlayStation Blogcast with Seth Killian, Nathan Drake from the Uncharted series nearly got in the game.

He commented: “We were committed to try and provide some extra content to Sony and we were excited about looking at the different roster and seeing who was out there, and you know you’ve got all sort of cool characters like Nathan Drake, but you know Nathan Drake has kind of a nice Han Solo kind of everyman and he’s a comical guy but the Japanese team got really excited about Cole and the flexibility of his powers, projectiles, grabs, and all sorts of cool stuff.”

Cole, Toro and Kuro all have continue animations for the Arcade Mode in the PlayStation 3 version of the game. Because neither of these characters are playable in this mode, these animations go unused.

When you encounter Cody Travers and Guy in Bryan Fury and JACK-X's story mode, Bryan asks JACK-X how strong their opponents are. Jack-X claims their power levels are over 9,000. This is a reference to a infamous meme from the "Ocean Dub" version of the Dragon Ball anime.

The Japanese version doesn't feature this joke.

When you encounter Steve Fox and Hwoarang in Hugo and Poison's story mode in the Japanese dub, Hugo says "I am number one!" while clearly pointing to himself. This was replaced with "We are number one!" in the English dub.

When talking about his working relationship with Yoshinori Ono, Katsuhiro Harada stated that he is someone who, "just kind of comes and goes as he pleases, and makes his own desk."