Finance chief Nick Humby and commercial executive Andy Anson have submitted their resignations and will leave the club in February 2007 to take up new positions.
Speculation has suggested the two have made the move after growing increasingly frustrated with the way their jobs had changed since Malcolm Glazer took over the club.
Chief executive David Gill said: "I am very disappointed to lose Nick and Andy.
"Nick has been an excellent finance director at the club for the last five years, getting involved in all areas of the business. His final major project has been to successfully manage the stadium expansion - delivering the best corporate facilities in football today - in time for the start of the new season.
"In his three years with the club, Andy has set a new commercial strategy for the club on which he has delivered excellently. He has played a lead role in our record shirt deal with AIG, as well as the negotiations to restructure our platinum partnerships and media businesses.
"Everyone at Old Trafford will join with me in thanking them for everything they have contributed and achieved and wishing them the very best for the future."
