Amstell was born on 29 November 1979 and was raised in Gants Hill, London. The lively and determined chap made his first television appearance in 1993 when he appeared as a contestant on the Channel 4 game show GamesMaster (1992-1998), which he unfortunately lost, but this did not falter him on his climb to fame, he went on appear on 'Good Morning with Anne and Nick (1992-1996)' doing an impression of Dame Edna Everage, and a 1994 episode of Family Catchphrase. In the latter, he described himself as a budding magician and showed one of his tricks to the presenter, Andrew O'Connor. Amstell and his family won a television and a video recorder.

Amstell started performing on the comedy circuit when he was just 13 and later caught the eye of television executives by becoming the youngest finalist of the BBC New Comedy Awards in 1998. His first professional television appearance was the same year, as a presenter on the UK children's channel Nickelodeon. He would later go on to co-host Popworld, with his quirky style of interviewing, he stirred controversy when discussing personal items with guests on the show.

Simon would later go on to become the second host of the comedic panel show 'Never Mind the Buzzcocks (1996-2015)' replacing Mark Lamarr.