The couple, who posted the news on their personal Twitter handles on Monday, said the decision was reached after due consideration.
The couple has been together for 27 years.
The two met in the late 1980s when Melinda joined Bill’s Microsoft firm. They have three children.
They jointly run the Bill & Melinda Gates Foundation.
The organization has spent billions fighting causes such as infectious diseases and encouraging vaccinations in children.
The Gates’ – along with investor Warren Buffett – are behind the Giving Pledge, which calls on billionaires to commit to giving away the majority of their wealth to good causes.
Bill Gates is the fourth wealthiest person in the world, according to Forbes, and is worth $124 billion.
He made his money through the firm he co-founded in the 1970s, Microsoft, the world’s biggest software company.
The pair both posted the statement announcing their divorce on Twitter.
“Over the last 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,” it read.
“We ask for space and privacy for our family as we begin to navigate this new life.”