Chief executive Wendy McMahon announced her resignation on Monday, according to several US media outlets, citing a memo to staff.
In the memo, McMahon described the past few months as "challenging", according to a report in the Washington Post.
She said it had become clear that she and the company had different views on the future direction of the broadcaster.
"The company and I do not agree on a path forward."
Last month, 60 Minutes veteran executive producer Bill Owens, left CBS News after Trump launched a billion-dollar lawsuit against the news magazine.
Trump accuses 60 Minutes of deceptively editing an interview with Kamala Harris, his Democratic opponent in last year's election campaign, allegedly swaying voter sentiment.
The New York Times reported that lawyers doubt the lawsuit's chances of success, but Shari Redstone, controlling shareholder of CBS News' parent company Paramount Global, is still seeking a settlement with the president.
This could also be due to Paramount's planned merger with Skydance Media, as authorities still have to approve the billion-dollar deal.
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