Ride made history in 1983 as a crew member on the space shuttle Challenger, breaking the gender barrier for U.S. spaceflight. Soviet cosmonaut Valentina Tereshkova became the first woman in space in 1963, but it took another 20 years for NASA to follow suit.
Word of Ride's death came in an announcement from Sally Ride Science, the educational venture she founded after leaving NASA.
President Barack Obama said he and his wife, Michelle, were "deeply saddened" by the news.
"As the first American woman to travel into space, Sally was a national hero and a powerful role model," Obama said in a White House statement.
NASA's deputy administrator, Lori Garver, said Ride "was a personal and professional role model to me and thousands of women around the world."
"Her spirit and determination will continue to be an inspiration for women everywhere," Garver said.
Ride was a mission specialist on her first mission, STS-7, which put the Canadian Anik C-2 and the Indonesian Palapa B-1 communication satellites into orbit. In an 2008 interview timed to coincide with the 25th anniversary of the flight, Ride acknowledged that her status as the first American woman "carried huge expectations along with it."
"I didn't really think about it that much at the time ... but I came to appreciate what an honor it was to be selected to be the first to get a chance to go into space," she said.
Thousands of spectators wore T-shirts and buttons emblazoned with the slogan "Ride, Sally, Ride" on launch day.
Ride made a second space shuttle flight in 1984, also aboard Challenger, and was in training for her third mission when Challenger exploded in 1986, killing all seven crew members. She left the space agency a year later, and served for years as a physics professor and director of the California Space Institute.
In 2001, she founded Sally Ride Science, a which is aimed at promoting math and science for girls. One of her projects was to develop a camera that could fly aboard spacecraft and take pictures for middle-school students. The fruits of those efforts include EarthKAM on the International Space Station and MoonKAM on the GRAIL lunar probes.
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