He was 95.
"We are saddened by the loss of Sen John Glenn, the first American to orbit Earth. A true American hero. Godspeed, John Glenn," NASA tweeted immediately after his death was announced.
Glenn died yesterday at the James Cancer Hospital in Columbus, Ohio, where he was hospitalised for more than a week, the John Glenn College of Public Affairs announced on its website.
The former astronaut had been battling health issues after suffering from stroke a few years ago. He had underwent heart valve replacement surgery in 2014. His death was confirmed by Hank Wilson, communications director of the John Glenn College of Public Affairs at the Ohio State University.
Known for his small-town decency and calm heroics, Glenn was the last survivor of the original Mercury 7 astronauts. He later served for nine years as a Democratic senator from Ohio.
On February 20, 1962, when Glenn rocketed into space, it was momentous and nerve-racking. Space travel was in its infancy. Every launch and mission captivated the imagination of America.
He made history a second time in 1998, when he returned to space decades later at the age of 77 only to become the oldest person sent into space.
In 1974, he was elected to represent Ohio in the US Senate. Two years later, Glenn's name was among those running mate for Democratic presidential nominee Jimmy Carter, but Carter ended up picking Sen Walter Mondale of Minnesota.
He also campaigned in the Democratic primary for the 1984 presidential election, but ended up losing to Mondale.
He was awarded the Presidential Medal of Freedom, the country's highest civilian honour, in 2012, by President Barack Obama.
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