In a statement released on the club's official website, the 55-year-old said his summer departure would allow United to "refresh themselves with new management and ideas".
It was also confirmed that executive vice chairman Ed Woodward would replace Gill as chief executive. Gill joined United as their finance director in February 1997 and assumed the role of chief executive in September 2003. He is to remain as a club director.
"It has been the greatest privilege to serve Manchester United for 16 wonderful years - the last 10 of which as its chief executive," Gill said.
"I have worked alongside the finest manager in the history of the game and been part of what I consider to be the best club in the best sport in the world.
"It has been a very hard decision because I love this club and, as the fans' banner says, it is, `more than a religion'. I've experienced some incredible highs, such as the Treble in 1999 and the League and Champions League double in 2008, and lows, like losing the title with the last kick of the season last year. But that is what makes this club and this sport so compelling.
"However, I have always been conscious of the fact that, as a member of staff, I was always just a temporary custodian of this marvellous institution. I am also of the view that all businesses need to refresh themselves with new management and ideas and after 10 years in charge I believe it is appropriate for someone new to pick up the baton."
Gill has enjoyed a fruitful working relationship with manager Sir Alex Ferguson and last year sanctioned the naming of a stand after him.
The Scot paid tribute to the outgoing Gill, who remains as the vice chairman of the Football Association and a nominee for the UEFA Executive Committee.
He admitted he had tried to persuade Gill to change his mind, saying: "I have been at United for over 26 years and for 23 of those years my boss has been one of only two men: Martin Edwards, who brought me to the club, and David Gill. I have enjoyed working with both."