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.

The tweet, which has since been deleted, read: "The Pride community is everybody, not just LGBTQ people. - Kayla, merchandiser."
June is being celebrated as Pride Month around the world, with parades in Los Angeles, Athens, and Rome among others.
The aim is to celebrate the gay community and fight for LGBTQ rights.
The tweet was meant to promote Abercrombie's limited edition tie-up with The Trevor Project, a free suicide prevention hotline for young LGBTQ people.
But despite the praiseworthy connection, many of the brand's Twitter followers found it inappropriate.
Blogger Camille Beredjick's rebuke was "liked" over a thousand times.
Activist Danielle Muscatoâ€

Robert McNaughton, 51, from Halesowen, set up fake Facebook accounts to troll the woman, West Midlands Police said.
The force said he was "hell bent" on destroying her life after she spurned his reconciliation attempts.
McNaughton, of Tenter Drive, was convicted after a trial of conspiracy to commit criminal damage.
See more stories from across Birmingham and the Black Country here
Sgt Chris Jones said: "McNaughton could not handle being rejected and became hell bent on destroying his ex-partner's life."
During December 2014 and February 2015, he bombarded her with abusive Facebook messages, threatening to release intimate images.
He also hired two men, Matthew Barker and Joden Smith, to carry out a string of attacks on her home, culminating with her car being set on fire in February 2015.
Barker, 44, of Leicester, admitted conspiracy to commit criminal damage and was jailed for 43 months.
Smith, 20, also of Leicester, admitted conspiracy to commit criminal damage and arson, recklessly endangering life and was sentenced to four years at a young offenders institution.
The men were sentenced at Wolverhampton Crown Court on 31 March.
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.
[NEXT_CONCEPT]
US clothing brand Abercrombie and Fitch has attracted an online backlash with a tweet seen by many as implying Gay Pride is not just for gay people.
[NEXT_CONCEPT]
A man who began a hate campaign against his ex-partner, which culminated in her car being petrol bombed, has been jailed for five years.