The TV presenter – who found fame on children's CITV in 2004 – has said she made the difficult decision "for my family.
But quitting This Morning does not mean the mother-of-three will be disappearing from the public eye completely.
So what will Willoughby do next?
Dancing On Ice
Willoughby is due to co-host Dancing On Ice for its 16th series, when it returns to ITV1 in January.
Phillip Schofield has stepped down from the show following his resignation from This Morning and there ahs been much speculation as to who will join Willoughby to present the reality series.
The celebrity contestants for 2024 - including S Club's Hannah Spearritt and Corrie's Ryan Thomas - have already been announced, with Willoughby saying on This Morning how much she is looking forward to seeing them on the ice.
Other presenting projects
Willoughby took a leave of absence from This Morning in 2022 to film survival show Freeze the Fear with iceman Wim Hof, which she co-presented with Lee Mack.
That year she also co-presented The Games with Freddie Flintoff, Chris Kamara and Alex Scott.
In 2018 she was chosen to join Declan Donnelly co-hosting I'm A Celebrity... Get Me Out Here! while Ant McPartlin was in recovery battling alcoholism.
So as Lorraine Kelly said: "Of course we will still see her. There will be lots more projects."
In 2021 Willoughby branched out as a lifestyle guru, launching her own website Wylde Moon.
It is described as "a lifestyle site and online boutique, inspired by Holly's fascination with the moon, covering interviews with inspiring women, beauty and fashion advice from Holly's team, an 'energy' section and life insights from the presenter."
The Wylde Moon boutique sells perfume, candles, wax melts and diffusers so fans can bask in the scent of their favourite TV star.
Having begun her career as a teen model Willoughby has been the face of Marks and Spencer's women's fashion since 2018.
M&S were among those to send their love and support on social media when she announced she was stepping down from This Morning, and their partnership appears to remain strong.
Willoughby signed a reported seven-figure contract in October 2022 to remain a brand ambassador at M&S for another two years.
Every day she would share details of her This Morning outfits on Instagram and dresses often sold out when worn by Willoughby.
The mother-of-three first branched out into the realm of celebrity author when she and her sister Kelly published their series of School For Stars children's books in 2014.
Willoughby has dyslexia and has often spoke publicly about her struggle with reading and writing, in a bid to raise awareness and inspire others.
She published her first book for adults Reflections in 2021. The self-help book about "finding beauty inside and out" saw Willoughby open up about body confidence, burn out and reclaiming her sexuality.
Willoughby has made several cameos over the years, playing herself in soap Coronation Street and a witch called Goody in a 2010 episode of Miss Marple.
Most recently the self-confessed whodunnit fan made a cameo appearance in Midsomer Murders.
Viewers were a little baffled by Willoughby's performance on the ITV detective drama. But that doesn't mean more acting appearances are not on the cards.
Willoughby said herself she is stepping down from This Morning for her family. She is mother to son Harry, 14, daughter Belle, 12, eight-year-old son Chester and dog Bailey with TV production boss husband Dan Baldwin.
The TV presenter always took time off from This Morning to spend the school holidays at home with her children. And producers supported her flexible working, making sure she was able to be there on the school run on her kids' first day back at school.
She told The One Show in 2021: "I feel guilty about everything... I think the problem with working mums is that I’m feeling guilty because I’m not there to drop my kids off in the morning because I have to go to work.
“I know I love my kids more than anything on this planet. So why am I thinking like that? And it’s because I believe that’s what everyone else is thinking."
So now that she does not have to be on TV four days a week, 38 weeks of the year Willoughby has even more time to be a devoted mum.
Read more: Holly Willoughby
Holly Willoughby quits This Morning after 14 years 'for me and my family' (BBC News, 5 min read)
From Queuegate to Philip Schofield: A timeline of Holly Willoughby’s tumultuous This Morning career (Independent, 7 min read)
Watch: Holly Willoughby quits This Morning