In identical tweets, the Microsoft co-founder and his wife said they had made the decision to end their marriage of 27 years.
"We have raised three incredible children and built a foundation that works all over the world to enable all people to lead healthy, productive lives," they said in a statement. "We ask for space and privacy for our family as we begin to navigate this new life."
The Gateses were married in 1994 in Hawaii. They met after she began working at Microsoft as a product manager in 1987.
Last year, Bill, 65, said he was stepping down from Microsoft's board to focus on philanthropy.
He was Microsoft’s CEO until 2000 and since then has gradually scaled back his involvement in the company he started with Paul Allen in 1975. He transitioned out of a day-to-day role in Microsoft in 2008 and served as chairman of the board until 2014.
Meanwhile, Melinda, 56, has increasingly built her profile as a champion of women and girls. The former tech business executive launched her private Pivotal Ventures investment and incubation company in 2015 and recently partnered with Mackenzie Scott (Jeff Bezos' ex-wife) for a newly announced equity challenge.
The couple's Seattle-based Bill and Melinda Gates Foundation is the most influential private foundation in the world, with an endowment worth nearly $50 billion. It has focused on global health and development and U.S. education issues since incorporating in 2000.
Bill was formerly the world’s richest person and the couple now has an estimated $130 billion in assets.
The Associated Press contributed to this report.