Enfield first came to public attention when appearing on Channel 4's Saturday Live as a number of different characters created with Paul Whitehouse. These quickly entered the national consciousness. Among these characters were Stavros, a Greek restaurant owner with markedly fractured English; Tory Boy, a pompous Conservative MP; and Loadsamoney, an obnoxious character who constantly boasted about how much money he earned. Loadsamoney spawned a hit single in 1988 and a sell-out live tour. As a foil to Loadsamoney Enfield and Whitehouse created the Geordie "Bugger-All-Money" and in 1988 Enfield appeared as both characters during the Nelson Mandela Birthday Tribute Concert at Wembley Stadium. In time Whitehouse and Enfield became disturbed that Loadsamoney was being seen in a positive light, rather than as a satirical figure, and they had him run over during a Comic Relief Red Nose Day show while leaving the studio after presenting host Lenny Henry with "the biggest cheque of the night" — a physically huge cheque for ten pence.

In 1989 Enfield realised a personal project, Norbert Smith - a Life, a spoof on British theatrical knights slumming in the film industry. He also provided voices for the British satirical puppet show Spitting Image.

In 1990 Enfield developed his BBC sketch show, Harry Enfield's Television Programme, later called Harry Enfield and Chums, with Whitehouse and Kathy Burke. Eschewing the alternative comedy style prevalent at the time, both versions of the show were indebted to early 70s comedians such as Dick Emery and Morecambe and Wise. Enfield and his co-performers created another group of nationally recognised characters for these shows, such as Stan and Pam Herbert, who use the catchphrase "We are considerably richer than yow", Tim Nice-But-Dim, The Scousers, Smashie and Nicey, Wayne and Waynetta Slob, Annoying Kid Brother, who grew into Kevin the Teenager, and two old-fashioned BBC presenters, Mr Cholmondley-Warner and Grayson.

In 1991 Enfield played Dermot in the sitcom Men Behaving Badly, originally on Thames Television. He left after the first series and was replaced by Neil Morrissey as Tony. Enfield is a professed fan of opera and fronted a Channel 4 documentary series on the subject.

After a short break from television Enfield signed a new contract with BSkyB, but produced only one series, which flopped badly. In 2002 Enfield returned to the BBC with Celeb, a new series based on the comic strip of the same title in Private Eye, as the ageing rockstar Gary Bloke. The timing was unfortunate for Enfield as almost simultaneously The Osbournes began on MTV, having been a sleeper hit in the United States. The Osbournes, depicting the dysfunctional and unconventional family life of the heavy metal singer Ozzy Osbourne, was effectively what Enfield was trying to satirise with Celeb. The Osbournes became successful in Britain, while Enfield's show disappeared quietly after only six episodes.

In 2002 Enfield was the first guest on the revamped version of BBC's Top Gear and also appeared on the show on 23rd November 2008. He came in at an "achingly" slow time of 2:01 on his first appearance and 1:49.7 on the 23rd November 2008. Enfield has also narrated various TV documentaries such as the Discovery Wings channel 'Classic British Aircraft'.

In 2007, he played Jim Stonem in the Channel 4 series Skins. He reprised this role in the second series in 2008, and the third series in 2009.