Beverley Callard, who plays Rovers Return landlady Liz McDonald, is leaving Coronation Street next year - 22 years after her first appearance.
Bosses say they plan an "exciting" storyline for Callard, who joined with street husband Jim - Charlie Lawson - and sons Steve and Andy in 1989.
Callard, 53, said she wanted to see "what life has to offer beyond Liz's famous mini skirts".
Callard previously left the show in 1998 before returning five years later.
"I've loved every minute of my second stint on the street, it's always a difficult decision to make the leap."
She added: "I'll miss everyone on the show but I'm looking forward to some new challenges and to see what life has to offer beyond Liz's famous mini skirts."