The 30-year-old actress will be reprising her role as Sonia Fowler when she returns to Albert Square in January, accompanied by her character's daughter, Rebecca.
She makes her comeback in what producers are calling a "gripping storyline" that centres around the women of the Butcher household.
Natalie said she was "extremely excited and honoured to be making a full-time return" to the soap.
"I feel so lucky as an actress to get back to my roots," she added.
Natalie, who first appeared on the programme in 1993, has made occasional guest appearances since her original departure, most recently in January 2011.
She is the latest addition to the cast under new executive producer Dominic Treadwell-Collins, who recently recruited Danny Dyer as the new landlord of the Queen Vic pub.
Viewers saw Sonia at the centre of a number of dramatic storylines over the years.
She gave birth to Rebecca, her daughter with Martin Fowler, after failing to realise she was pregnant, and then gave her up for adoption.
She and Martin later regained custody and moved to Manchester. However, Sonia's return will reveal how the relationship was been on the rocks.
Since leaving EastEnders, Natalie has appeared on reality shows Strictly Come Dancing and Celebrity Big Brother. She has also starred on the stage in productions including The Vagina Monologues and The Cherry Orchard.