Berry voiced his appreciation of the television themes of Ronnie Hazlehurst in an episode of Charlie Brooker's Screenwipe, and his band played out the Screenwipe Christmas special with a rendition of Hazlehurst's theme tune for 1980s British sitcom Sorry!.

Berry has recorded six studio albums: Jackpot (1995), Opium (self-released, 2008), the most recent four have been released on Eddie Piller's Acid Jazz Records: Witchazel (2011) , Kill the Wolf (2013), Music for Insomniacs (2014) and The Small Hours (2016). In 2017 a "companion piece" to The Small Hours entitled Night Terrors was released, featuring remixes by artists such as Saint Etienne. He stated in the first issue of Bearded Magazine in 2007 that he was producing and collaborating on new material with 1960s soul singer Geno Washington and was to record a new album. This would become Witchazel, which Berry originally released as a one-day only free download in March 2009. The album was later officially released as a CD and paid-for digital download.

Berry was born in Bromham, Bedfordshire, to Pauline (née Acreman) and Charles Berry. He has one older sister, Johanna. He attended Nottingham Trent University, where he received a BA in Contemporary Arts in 1997.

He began his career as a Runner before appearing in the video game magazine show Game Over on BSkyB's computer and Technology channel .tv, between 1998 and 1999. Though commissioned as an editorial show on the subject matter, episodes contained a large number of comedy sketches with Berry as the main performer. These showcased a wide range of characters, one of which was a Sketch about The Exorcist entitled "Fear Pushed Through the Ring". It was this Sketch and others like it that resulted in Berry, and producers Rik Henderson and Richard Pitt, being fired from the show.

Berry composed all the music for Snuff Box and Toast of London, as well as the music for AD/BC: A Rock Opera, which he co-wrote with Richard Ayoade. AD/BC was a half-hour parody of overblown musicals in general and Jesus Christ Superstar in particular, telling the story of the innkeeper who allowed Mary, Joseph, and the baby Jesus to sleep in his manger. AD/BC was broadcast in December 2004 and featured Fulcher and Mighty Boosh stars Julian Barratt and Noel Fielding. He also performed a song for an episode of Garth Marenghi's Darkplace entitled "One Track Lover", a spoof of cheesy romantic 80s songs.

In October 2007, Berry provided a brand new track "Cream Pie" to Bearded Magazine for readers to download for free, followed by a cover of the Blur song "Sing" in November 2007. "Cream Pie" is still available to supporters of Beardaid.

Until 2010, Berry presented a show on Absolute Radio, where he still performs various voiceovers and is described as "the voice of Absolute Radio". The now-defunct Matt Berry Podcast regularly featured in the Top Ten of the iTunes podcast chart, and its Producer Vince Lynch was nominated for Best Online Producer at the Radio Production Awards.

In 2011, he appeared in the music video for "Reset", a song from Route One or Die, the debut album from London-based experimental band Three Trapped Tigers.

In 2012, part of the Snuff Box theme appeared briefly in the film Dredd, the line "but it was bronze" playing from a computer terminal in the Grand Hall of Justice in the latter half of the film.

Berry played the title character in the 2013 Portlandia episode "Squiggleman."

In 2014, Berry appeared in the BBC 2 series House of Fools, written by and starring Reeves and Mortimer.

In 2015, he was the opening act for Steven Wilson's second Royal Albert Hall concert.

In 2017 he appears in the Pugwash music video for What Are You Like, though he does not perform on the recording.