Rooney was unable to keep Derby in the Championship last season after the crisis-torn club were hit by a 21-point deduction as punishment for financial issues.
In his first managerial role, Rooney impressively kept Derby in contention to avoid relegation into the final weeks of the season.
That valiant effort had suggested the 36-year-old would be able to lead Derby to promotion from League One next season.
But with Derby remaining in administration throughout a turbulent close-season, Rooney has opted to quit the Rams with the new campaign starting on July 30.
“Wayne Rooney has today informed Derby County Football Club that he wishes to be relieved of his duties as first team manager with immediate effect,” a club statement said.
Rooney, Manchester United and England’s all-time leading scorer, took charge at Derby in 2020 and had a year to run on his contract.
The former England captain was linked with an emotional return to Everton as manager last season after earning widespread praise for his work at Derby.
“Over the course of the summer I have been closely following developments regarding the ownership of Derby County,” he said.
“Today I met with the administrators to inform them of my decision that it was time for me to leave the club. In fairness to them, they tried tremendously hard to change my decision but my mind was made up.
“My time at the club has been a rollercoaster of emotions, both highs and lows, but I have to say that I have enjoyed the challenge.”
Fears over Derby’s future increased last week when American businessman Chris Kirchner withdrew his offer to buy the club.
But the sale of Pride Park to a local property developer David Clowes, who hopes to complete a takeover, has eased concerns that the club could go bust.
Regardless of the potential for new ownership, Rooney felt Derby would benefit from the new energy of a manager not worn down by the relentless negativity surrounding the club.
“Personally, I feel the club now needs to be led by someone with fresh energy and not affected by the events that have happened over the last 18 months,” he said.
“I will remember my time at Derby with great pride and affection and would like to thank all my staff, players and of course the fans for their incredible support.
“I will never forget you and hope to see you all again in the near future and in happier times.”
