He attended North Carolina State University, pursuing a degree in Communication and Film. He failed a course before graduation and left for New York City. His original goal was to pursue acting, although he eventually became a stand-up comic.

In 2001 Zach Galifianakis co-starred in the film, Out Cold. He has also had small roles in Corky Romano, Below, Bubble Boy and Heartbreakers.

Zach got his start on television in 2002 as the host of his own talk show, called Late World with Zach. He later stated in an interview with Brian Palmer that he saw his show once on TV and immediately cancelled his cable subscription. His next television role was a as a coroner named Davis in the FOX drama Tru Calling, which lasted from 2003 to 2005. He has also appeared many times on Jimmy Kimmel Live and has made two appearances on Reno 911! as "Frisbee".

More recently, Zach performed on a tour called the "Comedians of Comedy" with Brian Posehn, Patton Oswalt, and Maria Bamford. They chose to perform at live rock clubs as opposed to comedy clubs to try to reach a different audience. Much of the tour was taped, and has been featured in both a short-lived TV series on Comedy Central and a full length movie that has appeared at SXSW and on Showtime.

In 2006, Zach was featured in Fiona Apple's music video for the song, "Not About Love". In the video, he is seen lip syncing the lyrics to the song.

Zach also stars as Alan Finger on the new Comedy Central show Dog Bites Man.