Shipton, 62, who has been in over 350 episodes, will appear for the last time on the BBC One soap next year.
She first appeared on-screen in Casualty's pilot episode in 1986.
And audiences have seen Lisa "Duffy" Duffin come and go in the Emergency Department over the years.
Her storylines have explored issues such as sexual assault, HIV, suicide, grief, single parenthood, humanitarianism, mental health and most recently, dementia.
Shipton said: "Walking in Duffy's shoes through the years has taught me so much for which I'll be forever grateful.
"I'm honoured and humbled to have played this inspiring woman. With sadness, but a sense of completion, l say goodbye."
Simon Harper, executive producer of Casualty and Holby City, said: "Cathy's enormous contribution has not just been to Casualty but also to the national consciousness and the British television drama landscape.
"She has made Duffy into a comforting Saturday night icon, the caring, ideal NHS nurse millions grew up with - and whom you'd want to be looked after by in times of need.
"She's given us some of our most unforgettable stories and moments, not least of late in her heart-rending dementia storyline, and I simply cannot thank her enough."
Shipton will appear on-screen as Duffy until early 2020.