She said she was leaving to focus on family, but will remain part of the Radio 2 team and will give further details next year.
Announcing the news on her Tuesday show, she said: “After six years of fun times alongside you all on the breakfast show, I’ve decided it’s time to step away from the early alarm call and start a new chapter.
“You know I think the world of you all, listeners, and it truly has been such a privilege to share the mornings with you, to go through life’s little ups and downs, we got through the lockdown together, didn’t we?
“We’ve shared a hell of a lot, the good times, the tough times, there’s been a lot of laughter. And I am going to miss you cats.”
Scott Mills will replace Ball on the breakfast show following her departure next month.
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“Zoe and I have been such good friends now for over 25 years and have spent much of that time as part of the same radio family here at Radio 2 and also on Radio 1,” he said.
“She’s done an incredible job on this show over the past six years, and I am beyond excited to be handed the baton.”
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Hugging outside the BBC building on the day of the announcement, Ball said she was “really chuffed for my mate and really excited about it”.
Ball was the first female host of both the BBC Radio 1 and Radio 2 breakfast shows, starting at the Radio 1 breakfast show in 1998, and taking over her current Radio 2 role from Chris Evans in 2020 after he left the show.
She took a break from hosting her show over the summer, returning in September.
Ahead of her stint in radio, Ball – who is the daughter of children’s presenter Johnny Ball – co-hosted the BBC’s Saturday morning children’s magazine show Live & Kicking alongside Jamie Theakston for three years from 1996.
She has two children, Woody and Nelly, with her ex-husband, DJ and musician Norman Cook, known professionally as Fatboy Slim.
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Ball said in her announcement her last show towards the end of December will be “just in time for Christmas with plenty of fun and shenanigans”.
“While I’m stepping away from the Breakfast Show, I’m not disappearing entirely – I’ll still be a part of the Radio 2 family, with more news in the New Year,” she added.
“I’m excited to embrace my next chapter, including being a mum in the mornings, and I can’t wait to tune in on the school run!”
Helen Thomas, head of Radio 2, said: “Zoe has woken up the nation on Radio 2 with incredible warmth, wit and so much joy since January 2019, and I’d like to thank her for approaching each show with as much vim and vigour as if it were her first. I’m thrilled that she’ll remain an important part of the Radio 2 family.”
Mills, 51, got his first presenting role aged just 16 for a local station in Hampshire, and went on to present in Bristol and Manchester, before joining BBC Radio 1 in 1998.
He’s previously worked as a cover presenter on Radio 2, but this is his first permanent role on the station.