The network said in a one-sentence statement: “After a thorough and careful review of the allegations… Bill O’Reilly will not be returning.”
The presenter has been on holiday since April 12, and was seen shaking hands with Pope Francis at the Vatican on April 19.
Bill O’Reilly said it was “tremendously disheartening” to leave over “completely unfounded claims”.
More than 50 sponsors have withdrawn ads from his show, The O’Reilly Factor.
Pressure on Fox has mounted since recent reports that five women had received $13 million in payouts because of Bill O’Reilly’s behavior.
Bill O’Reilly, who has been with Fox News almost since its inception, has denied all of the allegations.
He said in a statement released after his dismissal: “It is tremendously disheartening that we part ways due to completely unfounded claims.
“But that is the unfortunately reality many of us in the public eye must live with today.”
Fox broadcaster Tucker Carlson will be taking over Bill O’Reilly’s slot, the company said in a follow-up statement.
In an internal memo sent to 21st Century Fox employees, the company wrote that the decision had been made after “extensive review done in collaboration with outside counsel”.
The letter – signed by Rupert Murdoch and his sons Lachlan and James – praised Bill O’Reilly as “one of the most accomplished TV personalities in the history of cable news”.
It added that Fox News was committed to “fostering a work environment built on the values of trust and respect”.
The O’Reilly Factor drew nearly 4 million viewers per night.
The most recent allegation came on April 18 when lawyer for a former African-American clerical worker at Fox alleged her client had been harassed by Bill O’Reilly in 2008.
Lawyer Lisa Bloom said the Fox News host had referred to the unidentified woman as “hot chocolate”.
“He would leer at her,” said Lisa Bloom.
“He would always do this when no-one else was around, and she was scared.”
Media-watchers say the allegations had become too much of a liability for 21st Century Fox.
A concern for the Murdoch family is their pending $14 billion deal to buy out satellite provider Sky, which is being scrutinized by British regulators.
Earlier this month authorities with the European Commission cleared 21st Century Fox to acquire the remaining 61% of Sky that it does not yet own.
Sources at the company tell US media that Rupert Murdoch was in favor of keeping Bill O’Reilly in his post.
However, 21st Century Fox CEO James Murdoch reportedly argued that Bill O’Reilly should go.
The company reputation has taken a hit after harassment allegations were also leveled at Roger Ailes, the former head of Fox News.
Roger Ailes resigned in 2016 after being sued by a former Fox News presenter, Gretchen Carlson.
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