The TV star, known for his surreal content and deadpan style, was a team captain on Jimmy Carr’s Channel 4 comedy panel show 8 Out Of 10 Cats and spin-off 8 Out Of 10 Cats Does Countdown.
He also wrote and starred in the popular BBC sitcom 15 Storeys High.
A statement from his agent Off The Kerb Productions said: “It is with great sadness that we have to announce the death of Sean Lock.
“He died at home from cancer, surrounded by his family.
“Sean was one of Britain’s finest comedians, his boundless creativity, lightning wit and the absurdist brilliance of his work, marked him out as a unique voice in British comedy.
“Sean was also a cherished husband and father to three children.
“Sean will be sorely missed by all that knew him.
“We kindly request that the privacy of his family and children is respected at this difficult time.”
Comedian Lee Mack, who was a close friend, paid tribute saying: “I’ve known this day was coming for some time, but it’s no less heart-breaking.
“A true original both in comedy and life. I will miss him so much.”
Born in Woking, Surrey, the comedy star left school in the early 1980s and began working on building sites but developed skin cancer, which he blamed on over-exposure to the sun. He made a full recovery and focused on a career in comedy.
One of his first professional TV appearances was in 1993, starring alongside Rob Newman and David Baddiel on their signature TV show Newman And Baddiel In Pieces.
He script-edited the 1998 BBC Two series, Is It Bill Bailey? and had his own show on BBC Radio 4 called 15 Minutes Of Misery, which was later expanded into TV series 15 Storeys High.
The show was set in a tower block and centred on a pessimistic character called Vince (played by Lock) and his flatmate Errol, played by Benedict Wong.
In 2005 Lock became a regular team captain on the panel show 8 Out Of 10 Cats, a role he held for 18 series.
Between 2006 and 2007 he hosted Channel 4 series, TV Heaven, Telly Hell, in which he invited celebrities to share their own selection of TV’s triumphs and tragedies.
Guests on the show included Alan Davies, Johnny Vaughan, David Mitchell, Bill Bailey, Johnny Vegas and Nick Hancock.
Speaking at the time, Lock told the PA news agency, he said: “I think one of my all-time favourite shows is Catchphrase with Roy Walker. I loved it. I used to like Roy’s restraint, because, for a comedian, the opportunity to take the mick out of some of the ridiculous answers could have been too hard to resist.”
Lock also appeared on panel shows including Have I Got News for You, QI, and They Think It’s All Over.
In 2000 he won the gong for the best live stand-up at the British Comedy Awards.