Ruud van Nistelrooy leaves Manchester United as Ruben Amorim takes charge
The Dutchman was hired as former boss and compatriot Erik ten Hag's new assistant in the summer ahead of the 2024/25 season.
He then stepped into an interim managerial role for the club after the former Ajax coach was sacked last month.
The United legend, who scored 50 goals in just 219 games between 2001 and 2006, remained unbeaten in his four games in charge at Old Trafford and signed off with a solid 3-0 win against Leicester on Sunday.
In a statement, the club thanked Van Nistelrooy for his most recent stint and also confirmed the exits of fellow coaches Rene Hake, Jelle ten Rouwelaar and Pieter Morel.
"Manchester United can confirm that Ruud van Nistelrooy has left the club," the statement said.
"Ruud rejoined in the summer and has taken charge of the team for the past four matches as interim head coach.
"Ruud is, and always will be, a Manchester United legend.
"We are grateful for his contribution and the way in which he has approached his role throughout his time with the club. He will always be very welcome at Old Trafford.
"Rene Hake, Jelle ten Rouwelaar and Pieter Morel have also departed and we wish them all well for the future.
"We will confirm the full men’s first team coaching composition in due course."
Van Nistelrooy, who joined the Red Devils in July on a two-year deal, managed three victories and a draw in his four games as caretaker boss.
New manager Ruben Amorim arrived in Manchester from Portugal on Monday.
Speaking after Sunday's victory, Van Nistelrooy thanked the club for the "amazing" opportunity.
"We said 'let's make the most of these four games', get the maximum out of it and I think we did an OK job," he said.
"I really enjoyed it, it's been a short but amazing period. We are in an uncertain position but we tried to do our jobs and help the club which is important.
"There are a lot of feelings there, the way the fans supported me and the team always in difficult moments it was a special moment. To close down this block of games with good results and a good connection I can't thank them enough."