The lease for the Chapters store operating in a renovated 80-year-old theatre at Bloor and Runnymede won't be renewed, a store spokesman told CBC.
In the early 1990s, many residents were opposed to the idea of the large book retailer setting up a shop in the much-loved former vaudeville theatre.
Former Mayor David Miller, who represented the ward at the time, said many residents didn't want changes made to the theatre which is a centrepiece of the Bloor West retail strip.
"People didn't want the theatre to go but if it had to go, they really wanted the heritage to be preserved," Miller recalled.
Since then however, the store has won over many of its opponents, largely because the store was able to renovate while preserving the theatre's heritage character.
Longtime resident Gwen O'Connell said the store's departure is bad news for the neighbourhood.
"I was devastated," she told CBC News. "I was thinking this community can change but we shouldn't forget about the community."
She says the bookstore has become a hub where high school choirs perform, mothers and children gather for reading groups and the community raises money for schools.
Some people in the community say they will fight to keep the bookstore open but that may be a losing cause. Chapters says when it moves out of the building, Shoppers Drug mart is moving in.
That means more change though the building's exterior is protected by historical designation.