Zissis was born on December 17, 1975 in New Orleans, Louisiana. He is of Greek descent. He attended the all-male Jesuit High School. Among his schoolmates were Mark Duplass and Jay Duplass; he knew both, although he was better acquainted with Mark, who was a year below him, than Jay, who was three years above him. Zissis was heavily into music and musical theater.
Zissis made his film debut in the short film Climbing Out (2002). He went on to star in The Intervention, a short film directed by Jay Duplass and written by Mark Duplass. Zissis then went on to appear in the short film Momma's Boy. In 2008, Zissis had the leading role in the film Baghead which was written and directed by Mark Duplass and Jay Duplass, which had its world premiere at the Sundance Film Festival on January 22, 2008. At the festival it was acquired by Sony Pictures Classics, and was released on July 13, 2008. That same year, Zissis appeared in the short film Loveolution, and made his television debut in The Office.
In 2009, Zissis appeared in The Overbook Brothers which had its world premiere at South by Southwest. That same year, Zissis appeared in Sunday Morning,
The League, and Prototype. In 2010, Zissis appeared in Cyrus. Zissis appeared in two episodes of Parks and Recreation. That same year Zissis wrote, directed, produced and edited the short film Kleshnov. In 2011, Zissis appeared in Jeff, Who Lives at Home, which was written by Mark Duplass and Jay Duplass. The film had its world premiere at the Toronto International Film Festival on September 14, 2011.

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