Thompson's Arnold Schwarzenegger impression first gained national attention during the California gubernatorial recall election of 2003. Posing as Schwarzenegger, Thompson phoned in to Fox News Channel's morning program, Fox & Friends, fooling the hosts into believing (at least for a short while) that he was, in fact, Schwarzenegger.

In April 2005, Thompson's "Fake Arnold" character proposed a fictitious plan to "blow up the moon". Fake Arnold's phony agenda managed to dupe MSNBC's Joe Scarborough, who appeared soon after on his television program, publicly lambasting the Governor for his alleged plan. Ten days later, after learning that the entire moon destruction scenario was a hoax, Scarborough apologized on-air for his erroneous comments.

On January 10, 2006, one day after Stern's show debuted on Sirius Satellite Radio, Thompson fooled Star Trek actor George Takei into believing he was actually speaking with Governor Schwarzenegger. Several minutes after the phone call with Fake Arnold ended, Takei was finally let in on the joke. One year later, the Takei prank was ranked sixth out of the Top 10 best moments from the show in 2006; it was also named as a top moment in the ten-year satellite tenure of the program. His final appearance was in June 2011.

In February 2007, Thompson made his first on-camera television appearance as Governor Schwarzenegger on The Late Late Show with Craig Ferguson on CBS. He became a regular performer on the show, making appearances as Robert De Niro, "Frat Guy", Brian Deese, and Levi Johnston, and as the voice of Morgan Freeman.

In 2010, Thompson appeared in advertisements for More Than insurance, doing his Morgan Freeman impression. In the advertisement, Thompson's character is named More Than Freeman.

Since 2011, Thompson has voiced various characters on both Family Guy and American Dad!. He also appeared on The Cleveland Show from 2011 until its cancelation in 2013.

Thompson has starred as narrator in Yogi Bear and Scary Movie 5, with on-camera appearances as lead character in the 2014 film, Nowhere Girl, and a supporting role as a priest in the 2017 film, Revelator. He was also featured in The Angry Birds Movie, voicing two characters. Thompson had also voiced a Construction Forman in the 2017 film, The Nut Job 2: Nutty by Nature

Thompson has also embarked on various podcasts throughout his career. The most recent installment, Joshin' Around, was picked up by iTunes in 2016, consisting of Thompson alone improvising all material.

During his junior year at Padua Franciscan High School, Thompson delivered one line for the school's production of Oklahoma! and walked off to laughter and applause. "Then someone backstage said, ‘They're clapping for you. They love you.' After that, I was hooked." Thompson and some of his classmates got a video camera and began making feature-length and short films, and television-style shows. He graduated from Padua in 1993.