Ed Woodward has resigned as Manchester United executive vice-chairman and will leave at the end of the year.
The 49-year-old joined the club in 2005 and becomes the first high-profile departure since plans for the now stuttering Super League were unveiled on Sunday evening.
Woodward's exit is understood to be amicable with the owners, the Glazer family, and he will continue in his role until the end of 2021.
"I am extremely proud to have served United and it has been an honour to work for the world's greatest football club for the past 16 years," the outgoing executive vice-chairman said.
"The club is well positioned for the future and it will be difficult to walk away at the end of the year.
"I will treasure the memories from my time at Old Trafford, during a period when we won the Europa League, the FA Cup and the EFL Cup.
"I am proud of the regeneration of the club's culture and our return to the Manchester United way of playing.
"We have invested more than £1billion in the squad during my time here and I am particularly delighted with the progress the players have made under the astute leadership of Ole Gunnar Solskjaer and his coaching team in the last two years.
"I am sure that with the changes we have made on-field and to the coaching and football staff in recent years this great club will soon be lifting silverware again. It deserves to.
"I desperately wanted the club to win the Premier League during my tenure and I am certain that the foundations are in place for us to win it back for our passionate fans."
Concluding a lengthy statement, Woodward said: "I would like to thank United's passionate fans for their support during the good and bad times.
"I know this has been a challenging period in our history, but your support for the team has never, ever been in doubt.
"Finally, it has been a pleasure to work with so many magnificent, talented and hard-working people."
Woodward made no mention of the Super League in his comments and it is reported that his exit his unrelated to the controversial plans.
The 49-year-old played a key role in the newfangled competition and was singled out for criticism by UEFA president Aleksander Ceferin.
News of the breakaway league has been met by intense and relentless criticism, with the Old Trafford giants among six Premier League clubs to join the 12-strong breakaway European competition.
United club co-chairman Joel Glazer was named as vice-chairman of the Super League, hailing it as a "new chapter" amid a storm of condemnation.
In a statement confirming Woodward's departure, Glazer said: "Ed Woodward has served the club with great distinction. On behalf of everyone at United I would like to place on record our sincere thanks for his tireless work and dedication.
"His contribution to the club has been massive, and he will always be welcome at Old Trafford as a part of the Manchester United family."