The news comes with the League One side in administration and in search of a new owner following their relegation to the third tier.
Manchester United and England legend Rooney joined the Rams as a player in 2020, and later took charge of the team, receiving huge plaudits for his work in the dugout.
The 36-year-old former striker kept the side in the Championship during his debut campaign in 2020-21, and attempted to stage a great escape last season despite crippling points penalties.
The club had to contend with a deduction of 21 points after former owner Mel Morris left, and eventually finished up in the relegation zone, seven points from safety despite Rooney's best efforts.
Derby fans have had a year from hell since being placed into administration in September 2021, with prospective buyers Erik Alonso and Chris Kirchner failing to live up to their promises and purchase the side, leaving it in purgatory ahead of the new season.
Rooney said of his decision: "Over the course of the summer I have been closely following developments regarding the ownership of Derby County.
"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."
Rooney added: "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.
"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.
"Finally, I am aware that the club still have interested parties who wish to take over the running of the club.
"To them I say this, Derby County is a great club with a great history and great fans. I wish you all the best and much success for the future."
Rooney had previously reaffirmed his commitment to the relegated Rams, but only if the club was able to find a new owner.
Speaking to fans outside of Derby's training ground following the club's relegation in April, Rooney said: "We're grateful for the support you've shown us all season. It's been f****** tough, been hard. Difficult moments for us, for you (fans) especially", Rooney said.
"But we've tried our best, we've given everything we can. It's unfortunate we've been relegated but now we'll plan to make sure this club comes back.
"The takeover has to happen," he said after the match. "If it doesn't I fear for the club. It has to (go through). If it happens, I want to rebuild the club. This is a special club, I've said all along. I want to try and bring the happy days back.
"In some ways we can draw a line under everything that has happened and really start the rebirth of this club. The quicker the takeover happens the quicker we can develop the squad.
"I feel for the players. We've taken 52 points and in normal circumstances we'd be safe by now. We've paid the price for what the previous owner has left behind.
"It's no-one's fault - not mine, not the staff, not the players' - other than the previous owner. We're paying the price and I'm sure it's a sad day for Mel (Morris) too because I know he's a Derby fan. I'm sure he'll be very disappointed."
Supporters are clearly still reeling from Alonso and Kirchner's failed takeovers, but the day had begun with some positivity.
Derbyshire businessman David Clowes has agree to buy their Pride Park Stadium and revealed he was preparing a bid to purchase the club.
The news came after the most recent update from the Football League, who revealed they were stepping in to aid the sale of the club following Kirchner's collapsed takeover.