Isaacson told staff at CNN that he had taken a "very tough decision" to leave. He will be replaced by Jim Walton, president and chief operating officer of CNN News Group.
Isaacson's departure came on the same day that Steve Case finally succumbed to pressure and stood down from his role as chairman of AOL Time Warner, which owns CNN. Isaacson is seen as having tried to modernise CNN, in an attempt to keep up with rival Fox News Network.
Recently there were plans to merge the news operations of CNN with Walt Disney's ABC, but these have faltered. ABC is since believed to be holding talks with the BBC to extend their news-gathering relationship.
Meanwhile, Richard Parsons, CEO of AOL Time Warner, has been tipped to add Case's role to his existing responsibilities. While some investors are keen for Parsons to take both roles, others are looking towards a non-executive director, with media mogul and CNN founder Ted Turner being one name mentioned.
Following in the wake of financial scandals such as Enron and WorldCom -- from which AOL Time Warner has not been immune -- there is a growing push on Wall Street to keep the chairman and CEO roles separate.
Whoever takes on the role of chairman of AOL Time Warner will find themselves facing calls for the business to be demerged. Despite heralding the merger of America Online and Time Warner in 2000 as a groundbreaking melding of old and new media, the deal is now widely seen as a failure.
CNN's Isaacson is to become the head of the Aspen Institute, a global forum.
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