Thomas Middleditch was born and raised in Nelson, British Columbia. He was put into a play in 8th grade that he said "changed everything," taking him from an indoorsy kid who was bullied, to becoming the funny, popular kid in high school, even being voted Valedictorian. He discovered improv in grade school from performing with a group called Theatresports.

After a brief stint in college, he relocated to Chicago where he took classes at The Second City and iO Theater, while also performing regularly.

While performing on a Second City cruise, he got an audition for Saturday Night Live. Though he didn't get cast, the routine he used in his audition landed him a network holding deal, and he moved to New York City.

While there, Middleditch began acting in commercials. In 2007 a sketch video for Chicken McNuggets he made with Fernando Sosa in Chicago was purchased by McDonalds and used as a commercial.

In 2010, he joined a CBS pilot Hitched, written by Josh Schwartz and directed by Rob Greenberg.

The following year, Middleditch made his first appearance in the web series Jake and Amir, in the episode "Jake and Amir: Doobs." He made several returns to the series including performing in "Jake and Amir: Doobs Part 2," "Jake and Amir: Doobs Part 3," "Jake and Amir: Movie Date," and "Jake and Amir: Movie Date Part 2."

In 2011, Middleditch joined the cast of the Paramount Pictures' comedy film Fun Size, directed by Josh Schwartz.

On television, he had a role on The Office‍ 's final season episode "The Farm."

He worked in a 2013 comedy fantasy film The Brass Teapot, directed by Ramaa Mosley. He also worked in a 2013 CBS Films coming-of-age comedy Toy's House, later re-titled The Kings of Summer.

In 2013, Middleditch joined HBO's comedy pilot Silicon Valley playing Richard Hendricks.

He has said that the pilot was written with him specifically in mind as the lead (the character was originally named Thomas Pickering; the latter being his mother's maiden name). This was a result of a "random" audio sketch he once made for a stand-up routine which he would animate himself and pitch to several people, including Mike Judge's production partners John Altschuler & Dave Krinsky, who would later create Silicon Valley.

For his work on the show, Middleditch has garnered a Satellite Awards nomination and two Critics' Choice Television Award nominations. The show won Best Comedy Series at the 5th Critics' Choice Television Awards.