He was 87 and died late Friday of complications from pneumonia, the space agency said.
Forty-three years ago, Young - then a Navy test pilot - tuned in on a small, black-and-white television at the Naval Air Test Center in Florida as President John Kennedy addressed the nation.
He ended up as one of NASA's most experienced flyers, becoming the first astronaut to fly into space six times, and the only one to enter space in each of the Gemini, Apollo and space shuttle programs. "Astronaut John Young's storied career spanned three generations of spaceflight; we will stand on his shoulders as we look toward the next human frontier", NASA Administrator Robert Lightfoot said. He was a stickler for safety, which benefited and exasperated Nasa officials.
He also commissioned the first mission of the American Space Shuttle in 1981. "He was always questioning what we were doing and why we were doing it".
Young was the only astronaut to have flown into space six times.
"The Moon is a very nice place", he had said.
Young orbited the moon in Apollo 10, and made a lunar landing with Apollo 16.
Returning to Earth, they set a record still not equalled by a manned vehicle, going 32 times the speed of sound, or 40,000 kilometres per hour. He spent three lunar nights on the surface and drove more than 25km in a lunar rover.
Gemini, Apollo, and Space Shuttle astronaut John Young has passed away
Retired Canadian astronaut Chris Hadfield echoed that on Twitter, saying "John Young is one of my heroes, an astronaut's astronaut, a fearless individual and a good friend".
He feared it would get him fired, Mr Young said.
Fellow astronaut Terry Virts tweeted that Young's "passion for space will be missed".
Young's fifth space mission was as commander of the inaugural flight of NASA's first space shuttle, Columbia, in 1981.
His Nasa career lasted 42 years, longer than any other astronaut's, and he was revered among his peers for his dogged dedication to keeping crews safe - and his outspokenness in challenging the space agency's status quo.
In his autobiography, he revealed that he felt responsible for the shuttle accidents of the Challenger (1986) and Columbia (2003).
"The technical truth always has to be told, and telling it regardless of the consequences was one of my personality traits that people who knew me well learned to put up with", Young wrote in Forever Young, his 2012 autobiography.
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There also was a raucous scene in the Bills' locker room after a win over Miami when they saw Dalton's touchdown pass. The team made the announcement on Twitter Thursday and said the gesture is for a "TON of thank you's from Buffalo".