Mills was born in Berkeley, California. He graduated from Cooper Union in Lower Manhattan, New York City. His mother died of brain cancer in 1999. A week after she died his father Paul came out as gay at the age of 75 and after 44 years of marriage. Five years later his father died of lung cancer. His father was an art historian and museum director.
He has also worked as a graphic designer on promotional material and album covers for such acts as Beastie Boys, Beck, Sonic Youth, and Ol' Dirty Bastard. In addition he has created graphics for X-Girl, Marc Jacobs, and currently produces his own line of posters and fabrics called Humans by Mike Mills.
Thumbsucker (2005) is his feature-film directorial debut, for which he also created the film posters. He followed this up with Beginners in 2010.
He has released some of his art/documentary photography works with the two books, Gas Book 11 (2003) and Humans (2006). In 2009, the popular Berlin-based culture magazine 032c devoted an issue to Mills. For the occasion Mills was interviewed by Nick Currie, best known for his work as Momus, in a piece called "Getting Through the New Depression."