The 45-year-old was only appointed in March 2024, but has failed to make a positive impact during his 11 months in the dugout at the Abbey Stadium.
After guiding The U's to 18th place last term, there was hope that the ex-Swansea manager could push for a top half finish this term.
Instead, Cambridge sit rock bottom in 24th spot in League One having lost 18 of their 31 matches.
And following the 1-0 home defeat to Exeter on Saturday, the decision has been made to part ways with the 2013 League Cup winner.
A statement from Cambridge's majority owner Paul Barry read: "We would like to thank Garry for his hard work and commitment to Cambridge United over the last 12 months.
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"He really bought into the club during his time with us and we are all very disappointed that it has not worked out in the way we would all have hoped.
"In the end, the table does not lie and it is the right moment to make a change as we conclude the first part of our football review.
"There are 15 games of this season remaining, and we must continue to fight together to preserve our League One status over the coming weeks.
"At the same time, we will use this period to plan strategically for the next chapter of the football club.
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"We will say more about this in the week."
Monk's first managerial gig came in February 2014, where he took charge of then-Premier League side Swansea on an interim basis following the sacking of Michael Laudrup.
He ended up getting the job on a permanent basis after guiding the Swans to survival with one game to spare.
And after winning the Premier League's Manager of the Month Award in August, Monk was regarded as one of the game's brightest up-and-coming bosses.
But just five months after signing a three-year deal in July 2015, Monk was axed by the Welsh outfit following a run of one win in 11 top-flight games to leave them in 15th place.
His 77 games in charge of the Swans is the most amount he has managed a single team, with Monk failing to spend more than 18 months at a club in his managerial roles since.
Following his Swansea exit he linked up at Leeds in June 2016, but resigned at the end of the season after the Whites finished seventh in the Championship.
After a year out, he then stayed in England's second-tier to take over at Middlesbrough, but lasted just six months having won just 12 of his 26 games.
Birmingham were Monk's next club, but he was sacked in June 2019 after 13 months in charge following a 17th-placed finish in the Championship.
And in what was Monk's last role before being appointed at Cambridge was at Championship outfit Sheffield Wednesday.
But just like at his previous clubs, he didn't last long, with his contract terminated in November 2019 after 13 months with the Owls 23rd in the table.
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