Larry Rudolph, who helped Spears secure her first recording contract, said the star's "intention to officially retire" had prompted him to resign.
The move comes two weeks after Spears told an LA judge that she had been forced to perform against her will.
She is currently seeking to end a conservatorship that has governed her life and finances since 2008.
Rudolph announced his intention to resign in a letter to the star's father, Jamie Spears, and co-conservator Jodi Montgomery.
"It has been over two and a half years since Britney and I last communicated, at which time she informed me she wanted to take an indefinite work hiatus," he wrote.
"Earlier today, I became aware that Britney had been voicing her intention to officially retire. As her manager, I believe it is in Britney's best interest for me to resign from her team as my professional services are no longer needed."
Rudolph noted that he had "never been a part of the conservatorship nor its operations, so I am not privy to many of these details," but said he was "incredibly proud of what we accomplished over our 25 years together".
"I wish Britney all the health and happiness in the world, and I'll be there for her if she ever needs me again, just as I always have been," he concluded.