Shrigley was born 17 September 1968 in Macclesfield, Cheshire. He moved with his parents and sister to Oadby, Leicestershire when he was two years old. He took the Art and Design Foundation course at Leicester Polytechnic in 1987, and then studied environmental art at Glasgow School of Art from 1988 to 1991. Talking about his final degree show, Shrigley later told The Guardian's Becky Barnicoat, "I thought my degree show was brilliant, but the people who were marking it didn't. I got a 2:2. They didn't appreciate my genius. I didn't sell anything at the show – it was 1991, before the YBAs. There wasn't a precedent for people selling work that wasn't figurative painting". Before becoming a full-time artist, Shrigley worked as a gallery guide at the CCA in Glasgow.
As well as authoring several books, he directed the video for Blur's "Good Song" and also for Bonnie 'Prince' Billy's "Agnes, Queen of Sorrow". In 2005 he designed a London Underground leaflet cover. Since 2005, he has contributed a cartoon for The Guardian's Weekend magazine every Saturday. Other projects have included the album Worried Noodles (Tom Lab, 2007) where musicians interpret his writings as lyrics, including collaborations by David Byrne, Hot Chip, and Franz Ferdinand.
Shrigley co-directed a short film with director Chris Shepherd called Who I Am And What I Want (2005), based on Shrigley's book of the same title, with Kevin Eldon voicing its main character, Pete. Shrigley also produced a series of drawings and t-shirt designs for the 2006 Triptych festival, a Scottish music festival lasting for three to four days in three cities. He also designed twelve different covers for Deerhoof's 2007 record, Friend Opportunity. In the same year he also designed the title sequence for the film Hallam Foe, as well as the drawings and the writing in Hallam's on-screen diaries.
In 2014, Jonathan Jones reviewed Shrigley's work Brass Tooth, writing, "David Shrigley must have had a big, toothy grin when he created multiple editions of his sculpture Brass Tooth, which goes on sale for £1,200 a pop at the London art fair this week. It is a cast of a single tooth – including the roots – and is typical of Shrigley's sly, subversive, humorous art in how it brings a modern art cliche crashing down to Earth".
In 2015, he designed "Kingsley", a mascot for Scottish football team Partick Thistle as part of a sponsorship deal. The mascot's design was the object of some amusement, with Scottish BuzzFeed reporter Jamie Ross describing it as "based on every nightmare I had as a child."
Shrigley also undertook a residency at Auckland's Two Rooms in 2015, during which he painted for the first time since his graduation from The Glasgow School of Art in 1991. He said that the residency presented ‘an opportunity to explore a different medium and explore what you can do with “that” versus what you do with “this”.’
Shrigley's sculpture Really Good was installed on Trafalgar Square's Fourth plinth in September 2016 until March 2018. The bronze cast of a fist with an out-of-proportion thumbs-up was the winning commission for the Fourth Plinth Project, which has been inviting artists since 1999 to make a proposal for the empty plinth, originally intended to hold an equestrian statue of William IV that was never made. "I made a drawing of an elongated thumb that said everything is good and I wrote some text that sounded like some sort of weird political satire: If we make this sculpture, we can make the world a better place through some kind of self–fulfilling prophecy.”
In 2019, he designed the yellow and red card of the AS Velasca. Shrigley was appointed Officer of the Order of the British Empire (OBE) in the 2020 New Year Honours for services to visual arts.