Her friend Cathryn Michon says that Wallace died "due to complications from breast cancer of which she was a long and proud survivor and advocate for women and healing," according to Deadline.
The Emmy-winning actress, who found fame as Newhart's foil Carol Kester in his 1970s sitcom, was first diagnosed with breast cancer in 1985.
"Cheers to the hilarious, kind, fab Marcia Wallace, who has taken her leave of us," Tweeted Yeardley Smith, who voices Lisa Simpson. "Heaven is now a much funnier place b/c of you."
Simpsons producer Al Jean said in a statement to Entertainment Weekly that the show planned to retire Wallace's school teacher character.
"I was tremendously saddened to learn this morning of the passing of the brilliant and gracious Marcia Wallace," he said. "She was beloved by all at The Simpsons and we intend to retire her irreplaceable character."