While studying at Northbrook College Worthing, Hewlett, Alan Martin and fellow student Philip Bond created a fanzine called Atomtan. This brought him to the attention of Brett Ewins. After leaving college Hewlett and Martin were invited by Ewins to create material for a new magazine he was setting up with Steve Dillon in 1988.

By 1992, Hewlett had become a major creator in the comics industry, and one of the few to break into mainstream media. He had worked with writer Peter Milligan on Hewligan’s Haircut in 2000 AD issues 700 to 707. The series was later compiled into a trade paperback. He was involved in providing covers and art for Shade, the Changing Man, also written by Milligan, for DC Comics.

Tank Girl was optioned to be made into a film by MGM after being considered by, among others, Steven Spielberg. The film was released in 1995 and featured Lori Petty as Tank Girl. It was a commercial and critical failure and was criticised by fans who said it failed to capture the essence of the original strip. Hewlett had very little involvement with the film.

Deadline was eventually cancelled in 1996 due to falling sales in a changed market and Hewlett concentrated on working in advertising and designs for television, most notably the children’s series SMTV Live, featuring Ant & Dec. He also created the strip Get the Freebies, which was published monthly in British fashion magazine The Face. The stories, all set in London, followed the exploits of Terry Phoo, a gay, Buddhist kung-fu law enforcement officer and his sidekick Whitey Action, an enigmatic young anarchist with a bad attitude, as they tackle their primary adversaries The Freebies Gang. The dynamic between the two heroes was much like that of Tank Girl and her mutant kangaroo boyfriend Booga, with the episodes from the female protagonist’s point of view. The strip’s primary function was for Hewlett to vent his spleen against the media idols and trends of the day, the story often taking second place to the jokes.

At this time, he had moved into a flat with Blur’s Damon Albarn after Hewlett split with Oliver, and it was while sharing the flat that the pair came up with the idea of Gorillaz, a virtual band. Albarn would work on the music, while Hewlett would come up with character designs, and both came up with ideas for the members of the band. The first Gorillaz EP was released in 2000 followed by the first album, Gorillaz in 2001. In 2005, their second full studio album, Demon Days was released.

In January 2006, Hewlett’s artwork for Gorillaz was shortlisted for the Design Museum’s Designer of the Year award. In May 2006, he was named the Designer of the Year 2006. On 25 May 2006, Hewlett and Albarn won the joint award for Songwriters of the Year at the Ivor Novello Awards.

In 2007, Hewlett and Albarn premiered their first major work since Gorillaz, entitled Monkey: Journey to the West, a re-working of the ancient Chinese legend Journey to the West. Albarn wrote the score whilst Hewlett designed the set, animations and costumes. Written and adapted by Chen Shi-zheng, the show featured 45 Chinese circus acrobats, Shaolin monks and Chinese vocalists. It premiered at the Palace Theatre, Manchester as part of the Manchester International Festival, on 28 June 2007.

His Get the Freebies strip was adapted by BBC Three for a pilot entitled Phoo Action, broadcast in February 2008.

He married French presenter and actress Emma de Caunes at Saint-Paul-de-Vence on 10 September 2011.

In a 2012 interview for Absolut Vodka, Hewlett also listed Harvey Kurtzman’s American satirical magazine MAD Magazine as a leading influence of his art. Hewlett has mentioned that he is largely influenced by the works of American animator Chuck Jones of Looney Tunes, and cites the works of British comic book artists Ronald Searle and Mike McMahon as influences on his artwork. In fact, Hewlett has even stated that the entirety of Chuck Jones’ filmography and Mad Magazine as a whole are the biggest overall influences on his work.

During a 2012 Interview with Alfred Dunhill, he also lists the first film of the Star Wars series as another main influence on his artwork.

In a 2013 interview with Consequence of Sound, Hewlett stated that his primary influences were the works of cartoonists such as Mort Drucker, Carl Giles, Jack Davis, and Ronald Lowe.

A 2014 Kickstarter campaign successfully raised the capital for a new Tank Girl book called 21st Century Tank Girl featuring co-creators Hewlett and Martin, as well as other artists, including Brett Parson, Warwick Johnson-Cadwell, Philip Bond, Jim Mahfood, Craig Knowles, and Jonathan Edwards.

In November 2015, Hewlett debuted his first art exhibition called The Suggestionists at the Saatchi Gallery in London. The exhibition then made its American debut at the Woodward Gallery in Manhattan in May 2016.