Cera, the middle child of three siblings, was born in Brampton, Ontario, Canada, the son of Linda and Luigi Cera, a Xerox technician.[2][3] Cera's father is Sicilian.[2] Cera has two sisters and, as of 2007, still lives with his parents in Brampton.[3] He's attending Heart Lake Secondary School.[2] His first role was in a Tim Hortons' Summer Camp commercial.[2] Cera is currently dating Charlyne Yi, who played the stoner girlfriend in the film Knocked Up.

Cera played the young Chuck Barris in Confessions of a Dangerous Mind in 2002 and provided the voice for Brother Bear in The Berenstain Bears animated series and voiced Josh Spitz in the cartoon Braceface. He played George Michael Bluth in the award winning television series Arrested Development for three seasons before it was cancelled.[6] In 2005, he starred as Harold in the award winning surreal humour short film Darling Darling, for which he was awarded Best Actor at the San Gio Festival in Verona, Italy. In late 2006, he created and starred in a parody of the YouTube video Impossible is Nothing, a video résumé created by Aleksey Vayner.[7] He also guest-starred in an episode of teen noir drama Veronica Mars (in the episode The Rapes of Graff, which also featured Arrested Development co-star Alia Shawkat), and also in the Adult Swim series Tom Goes to the Mayor and Tim and Eric Awesome Show, Great Job!

Cera, along with Clark Duke, wrote and starred in a series of short videos released on their website.[6] In 2007, they signed a deal with CBS Television to write, produce, direct, and act in a short-form comedy series entitled Clark and Michael.[8] The show featured guest stars such as David Cross, Andy Richter and Patton Oswalt, and was distributed via CBS's new internet channel, Innertube.[9] Cera also appeared in a staged comedy video that shows Cera being fired from the lead role of the film Knocked Up, after belittling and arguing with the director, in a scene that mocks the David O. Russell blow up on the set of I Heart Huckabees.[6] Another clip featured actor James Franco in a similar situation. Cera starred alongside Jonah Hill in the hit # 1 movie Superbad, which was written by Seth Rogen and Evan Goldberg. The film, which opened in North America on August 17, 2007, is semi-autobiographical, with Cera playing a character named Evan. In November 2007, Cera hosted Saturday Night Live on strike, a version of SNL not shown on TV due to the 2007 Writers Guild of America Strike.[10] Also in the same year, Cera co-starred in Juno (written by Diablo Cody and directed by Jason Reitman), playing Paulie Bleeker, who unexpectedly gets his long time teenage friend Juno (Ellen Page) pregnant.