The foundation of Deayton's career was a parody of British local radio stations, Radio Active, broadcast on BBC Radio 4 between 1981 and 1987, which he both co-wrote and performed in. It transferred to television as KYTV between 1989 and 1993.
Deayton presented a tribute to Radio Active and KYTV colleague and friend (and long-time BBC producer) Geoffrey Perkins for BBC Radio 4 on October 4, 2008. During this period, Deayton was also frequently seen appearing as a straight man alongside Rowan Atkinson. He starred with Atkinson in two separate roles (a pool attendant and a man on a park bench) in one of the earliest episodes of Mr. Bean and appeared opposite Atkinson in the Black Adder episode "Born to be King" (1983) as one of the Jumping Jews of Jerusalem, a kind of medieval variety act. He also appeared regularly in comedy sketches on Alexei Sayle's Stuff.
In 1990 Deayton was cast as the Meldrews' neighbour Patrick Trench in the British suburban sitcom One Foot in the Grave and was selected as the host of Have I Got News for You.
Deayton's suave manner as host of Have I Got News for You led to him being nicknamed "TV's Mr Sex", by a Time Out listings writer. He was much in demand as a presenter of television specials including the BBC's New Year's Eve show and the BAFTA Awards. He also featured in a series of advertisements for credit cards and the films Savage Hearts and Elizabeth. He was in one episode of Coupling where he appeared in a fantasy sequence alongside Mariella Frostrup.
In May 2002, the News of the World newspaper published allegations about his private life. He was ridiculed mercilessly by Paul Merton and Ian Hislop, (as well as Ken Livingstone and comedian Dave Gorman) in the following episode of Have I Got News For You, but was allowed to continue as presenter. After a second round of allegations emerged in the papers the following October, Deayton was fired as presenter two episodes into the new series of Have I Got News for You. Since then, the show has been hosted by a different guest presenter each week.
Deayton is associated with the Comic Relief/Sport Relief charity and has featured in many of its TV broadcasts.
After being forced out of Have I Got News for You, he continued to work on other projects including a reunion of the Radio Active cast in a new episode broadcast in December 2002. In 2003, he guest-starred as Downing Street's top spin doctor in an episode of the BBC comedy Absolute Power, starring Stephen Fry and John Bird. He starred in BBC comedy Nighty Night which was shown from January 2004. A few months later, he made a return to presenting with ITV's cookery reality show Hell's Kitchen and then the light-hearted quiz Bognor or Bust. In January 2006 he hosted an ITV show based upon self-help videos called Help Your Self.
Deayton appeared for the England team as a second-half substitute in the Soccer Aid football match in support of UNICEF on May 27, 2006. He returned as a starting player for England in the September 7, 2008 rematch.
He also co-presented the BBC Sport Relief charity programme Only Fools on Horses in July 2006.
In 2007 he made an acting appearance in Casualty, playing an exaggerated version of himself in a Comic Relief-related storyline.
Deayton returned to the BBC in June 2007 hosting a new TV comedy panel game, Would I Lie To You?. In November 2007, he was censored by the BBC for making a "pungently personal" joke about Sir Jimmy Savile and his late mother on the show.
Deayton was also selected by ITV to be the host of the third series of Hell's Kitchen, which started broadcasting on September 3, 2007 at 9:00pm.
He also presents Comedy Sketchbook, a nostalgic look at classic comedy sketches, on BBC1.
It has been confirmed he will take over from Jonathan Ross as presenter of the British Comedy Awards. He presented the 2008 awards on 6th December 2008.