The actress, 33, has played feisty Alicia Metcalfe since joining the cast in 2010.
ITV announced the news over the bank holiday weekend, with Natalie later thanking fans for their messages of support.
A statement on ITV.com read: "Natalie Anderson will leave Emmerdale later this year after playing Alicia Metcalfe for 5 years.
"Following a stint in prison after assaulting Val Pollard and surviving a near-fatal gun wound at the hands of being shot by Cameron Murray, Alicia hasn't had an easy ride.
"All that would pale in comparison to the hardships faced following the sexual abuse Alicia experienced at the hands of Lachlan."
Soap fans have since seen Alicia make the big decision to make a new start for herself and her family in Portugal.
Speaking to Natalie regarding her departure, she says: "I've had the most incredible five years at Emmerdale and made some wonderful friends.
"I'm so grateful to the writers, directors, producers and everyone I've worked with.
"This year has been such a highlight and so amazing that I felt now was the right time to say bye to Alicia and see what the future holds."
Earlier this year, she was nominated for Best Actress at the 2015 British Soap Awards.
Natalie, who previously starred in ITV1's The Royal, is married to James Shepherd, with whom she has two-year-old son Freddie.
She also thanked fans via Twitter saying: "Thank u so much for the lovely msgs, n 4 the continued support for myself and Alicia ova the years, I'm v grateful n Ive loved playing her.."
She added: "I will be v sad to say goodbye to both her and @emmerdale. Xx"
I will be v sad to say goodbye to both her and @emmerdale. Xx— Natalie Anderson (@AndersonNatalie) May 24, 2015
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