The two were the original team captains on the show and ITV have confirmed they will be taking part in its last ever recording.
They will join host Keith Lemon as well as current captains Laura Whitmore and Emily Atack and a number of other special guests including Maya Jama, Joey Essex, Will Mellor, Johnny Vegas, Big Narstie and Chris Ramsay.
Willoughby and Cotton will star in the show's penultimate episode entitled The Happy Ending which ITV is labelling an 'incredible send-off celebration' for the long-running series which concludes in December.
A statement added: "The unpredictable, laugh-out-loud panel show will see a host of familiar faces return, to play some of the most popular games of series gone by, with a few additional surprises for viewers on the way."
Read more: 'Celebrity Juice' is ending after 14 years
Celebrity Juice's last ever episode will be a one hour compilation special of the show's best moments from its 14 year run on ITV2.
Ahead of the specials, Lemon has said: "But as always there comes a point when the party has to end. It’s been the most ace times and we’re gonna go out with a bang!….tidy!"
Celebrity Juice originally began airing in 2008 with Lemon, Willoughby and Cotton. There have been a number of other captains and panellists since Cotton and Willoughby left in 2018 and 2020 including Kelly Brook, Paddy McGuinness and former Spice Girl Mel B.
The show has simultaneously won Worst British TV Panel Show at the British Comedy Guide Awards and Best Entertainment Show at the TV Choice Awards.
Celebrity Juice: The Happy Ending airs on Thursday, 8 December at 10pm on ITV2 and ITVX, while Celebrity Juice: The Last Hurrah airs on Thursday, 15 December at 10pm.
Watch below: Maya Jama favourite to replace Laura Whitmore on Love Island