Executive producer Al Jean said in a statement to the New York Times that Shearer had turned down a new pay deal.
The show "will go on" and the actor's characters will be recast, Jean added.
Shearer took to Twitter to say the decision "wasn't about money" and that signing up to a new series would have stopped him from doing other work.
The 71-year-old provided the voice for addled school principal Seymour Skinner as well as rapacious millionaire Montgomery Burns and Ned Flanders, Homer Simpson's chipper neighbour.
Shearer signalled his exit on Twitter by claiming that a lawyer for executive producer James L Brooks said: "Show will go on, Harry will not be part of it, wish him the best."
In a follow-up tweet, Shearer added: "This because I wanted what we've always had: The freedom to do other work. Of course, I wish him the very best."
In response, Al Jean wrote: "Harry Shearer was offered the same deal the rest of the cast accepted, and passed.
"The show will go on and we wish him well. Maggie took it hard.
"We do not plan to kill off characters like Burns and Flanders but will recast with the finest voiceover talent available."
Last week, the Fox network confirmed it had commissioned two more series of the long-running animated sitcom.
According to reports at the time, Shearer had yet to sign a new contract.
On Thursday, the actor stressed that he had no plans to retire, adding: "On to new stuff..."
His other roles have included bass player Derek Smalls in rock "mockumentary" This is Spinal Tap.
The Simpsons has been on air since 1989, and the new series will take the total number of episodes to 625.
Harry Shearer, who voices Ned Flanders and Mr Burns in The Simpsons, is to leave the show after more than 25 years following a dispute with producers.