The actress, 46, will revive her role as mouthy Bianca Jackson after a five-year break from the soap.
Her return is a key signing for new show boss Kate Oates.
EastEnders viewers will see Bianca, who made her debut 25 years ago, reunited with troubled daughter Tiffany, played by Maisie Smith.
A soap insider said: “Bosses are delighted to be getting Patsy back. She’s a real Enders icon and fans love seeing old faces return.
“She has yet to get her scripts but she will no doubt be at the centre of drama when she returns in the autumn.
“She starts filming in the next few weeks and can’t wait to get going again.”
Patsy joined EastEnders in 1993, left in 1999, and returned for a second stint in 2008 before quitting again in 2014.
Bianca’s wedding to Ricky Butcher, played by Sid Owen, in 1997 drew one of the biggest soap audiences ever — more than 22million.
Patsy has been nominated for multiple awards for her performances as Bianca.
After quitting in 2014, the mum of four moved to LA to spend more time with her family and husband Richard Merkell.
Jon Sen, EastEnders’ exec producer, said: “I’m thrilled Patsy’s agreed to return to reprise her iconic creation in a blistering storyline that will grip fans this autumn.
"When I joined the show in January, bringing Bianca Jackson back to the Square was high on my wish-list. I'm thrilled to announce that Patsy’s agreed to return to reprise her iconic creation in a blistering storyline that will grip fans this autumn. There is no one more excited than me to see her step back into Albert Square again. I simply cannot wait.”