Matt was initially a physician by his profession. Later he started his career as a standup comedian with the group by the name The Groundlings as a part-time job along with his doctor profession. However, in the year 2002, he completely shifted as a full-time Comedian. In his career as a Comedian, he performed many shows of USO in Afghanistan, Bosnia, Hungary, and South Korea.
Gradually, he moved into the television work. He started hosting game shows like Scream Play and Casino Night on E! and GSN channels respectively. Consequently, he hosted many TV shows such as Clean House, Outtakes, American Ninja Warrior, The Drew Carey Show, General Hospital, NCIS, and much more popular shows.
Iseman is the winner of Daytime Emmy Award for Outstanding Special Class Special ad has gained huge fan followers.