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The Britain’s Got Talent judge said appearing in the hit programme from Down Under was a “simply fabulous” opportunity.
The star will play Harriet, the sister of the late Prue Wallace (Denise Van Outen) and the aunt of Harlow Robinson - who is played by Neighbours legend Jason Donovan's daughter Jemma.
The pair will be at the centre of a special London storyline which will be shot around the capital over the next few days.
“Like most people in the UK who were around in the late 80s/early 90s, I grew up watching Neighbours every single day of the week,” said Holden, 50, in a statement.
“I was glued to our TV for the wedding of Kylie and Jason (Scott and Charlene) while cursing Mrs Mangel and praying that Mike and Jane would eventually get together! Not to mention all the other greats over the years.
“To now have the opportunity to be a part of such an iconic Australian show is simply fabulous!”
Holden said she was excited to work with Jemma in London.
“This feels like a joyous occasion for everyone,” she added.
Jemma, 21, said she was “beyond excited” about filming with Holden.
The storyline will see Harlow and Harriet reunited in London, where they set about trying to solve a family mystery involving Prue.
Neighbours fans were excited to hear about Holden’s guest role.
“Amanda Holden is the perfect choice for the role, she will do us proud,” said one person on Twitter, while another called it “amazing news”.
The scenes will air next year.
Watch: Amanda Holden was encouraged to steal food