After graduating from university, the duo did two-man shows at the Edinburgh Fringe Festival and some sketch writing, including a series of Big Train and also for Armstrong and Miller's eponymous show. Their big break came in 2000 when they joined the writing team for the BBC Two sketch show Bruiser. The following year, the short-lived Play UK channel invited them to write their own sketch show, The Mitchell and Webb Situation. Later, they wrote and starred in the Radio 4 sketch show, That Mitchell and Webb Sound – which was later adapted for television on BBC Two as That Mitchell and Webb Look. The first series of That Mitchell and Webb Look won the BAFTA for "Best Comedy Programme" in 2007. They often appear with Olivia Colman, James Bachman, Mark Evans and Paterson Joseph. In 2008, the duo wrote a pilot script for their first original sitcom, Playing Shop. The two star as Eric and Jamie, friends who set up a business together after they are made redundant from their old jobs. Hartswood Films recorded the pilot episode on 20 December, with a view to producing a full series for BBC Two. Although approved by BBC, plans for future episodes fell through as Mitchell and Webb decided not to proceed with it. Mitchell and Webb collaborated with Armstrong and Miller again for the 2009Red Nose Day fundraising event. They co-wrote and starred in two short sketches incorporating Armstrong and Miller's World War II airmen characters from The Armstrong and Miller Show and their characters Sir Digby and Ginger from their radio showThat Mitchell and Webb Sound. In 2012, the pair provided the voices for the pair of robots in the Doctor Who episode "Dinosaurs on a Spaceship" in addition to starring in the BBC Two comedy-drama Ambassadors. In 2017, they appeared in the Channel 4 sitcom Back, on which they also worked as executive producers.
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Mitchell and Webb have also appeared in the U.K. regional versions of the 'Get a Mac' advertisements for Apple. They also voiced a pair of peas on the Ant and Dec's Saturday Night Takeaway sponsorship adverts for Birds Eye. Magicians, a film starring the pair was released on 18 May 2007. They have also released the book This Mitchell and Webb Book.