In an interview with Indie Game: The Movie he explains that his family was consistently riddled with alcohol and drug addiction.

[12] McMillen was the original character artist and animator on Braid,[12] before those assets were replaced by the work of David Hellman.

[17] McMillen and programmer Tommy Refenes established Team Meat, an independent game production company, with the intent that they would never utilize a third-party publisher.

[21] McMillen and Refenes responded to the success of Super Meat Boy and the impossibility of a sequel in a brief statement that read, "We feel like we did it right the 1st time.

"[22] McMillen and Refenes' development of Super Meat Boy was featured in the film Indie Game: The Movie.

Players control Isaac or one of 33 other unlockable characters through a procedurally generated dungeon in a roguelike manner, fashioned after those of The Legend of Zelda, defeating monsters in real-time combat while collecting items and power-ups to defeat bosses and eventually Isaac's mother.

The game was the result of a week-long game jam between McMillen and Himsl to develop a The Legend of Zelda-inspired roguelike that allowed McMillen to showcase his feelings about both positive and negative aspects of religion that he had come to discover from conflicts between his Catholic and born again Christian family members while growing up.

[1][26] McMillen had considered the title a risk but one he could take after the financial success of Super Meat Boy,[26] and released it without much fanfare to Steam in September 2011, not expecting many sales.

[27] Developer Nicalis worked with McMillen in 2014 to complete a remake of the game, The Binding of Isaac: Rebirth, bringing additional features that McMillen had planned that exceeded Flash's limitation, as well as to improve the game's graphics and enable ports for other systems beyond personal computers, including PlayStation 4 and Vita, Xbox One, Wii U, Nintendo 3DS, and the Nintendo Switch.

In 2016, McMillen announced a prequel to The Binding of Isaac titled The Legend of Bum-bo, independently developed by programmer James Interactive and himself.

[32][33] The End Is Nigh is a platform adventure video game developed by Edmund McMillen and Tyler Glaiel.