ITV has confirmed that the actress, who has played Hayley Cropper for 15 years, will leave to explore new projects.
"I've had the most wonderful and happy time in the life-changing 15/16 years I've been in Corrie, and I owe so much to the show and the special team that make it happen," Hesmondhalgh said.
"The decision to hang up Hayley's red anorak was a tough one, but doing the play at the Royal Exchange last year made me realise that there's life in the old dog yet (!) and that there are other things I want to try."
She added: "Whatever happens next I'll always be proudest of lovely Mrs Cropper and in particular what we achieved in changing attitudes to transgender and in portraying possibly the most loving, faithful and steadfast couple in soap history! I'll always be the show's biggest fan."
The show promised that its writers and producers were "working on storylines to ensure a dramatic exit plot for such an iconic character".
Executive producer Kieran Roberts said: "Who doesn't love Hayley Cropper? The character's warmth and decency, spiced with a great sense of fun and adventure, have put her at the heart of Coronation Street.
"The enduring popularity of and affection for Hayley - and of course her wonderful partnership with Roy - has so much to do with the brilliant way Julie Hesmondhalgh has brought the character to life on screen for the past 15 years.
"We'll be sorry to say farewell to Hayley - and to Julie - but we're planning a screen exit worthy of a one of Coronation Street's best-loved characters."
Hesmondhalgh joined the soap in 1998 as transsexual Hayley Patterson who met and eventually married cafe owner Roy Cropper (David Neilson).
The actress said last summer that she was "really grateful" to the soap for allowing her time off to appear Black Roses at Manchester's Royal Exchange. Get the Inside Soap magazine on your iPhone or iPad