Propelled to stardom by his 1988 book A Brief History of Time, which became an unlikely worldwide bestseller, Hawking dedicated his life to unlocking the secrets of the universe.
His genius and wit won over fans from far beyond the rarified world of astrophysics, earning comparisons with Albert Einstein and Sir Isaac Newton.
Hawking died peacefully at his home in the British university city of Cambridge in the early hours of Wednesday morning.
A university source told AFP that his health deteriorated around Christmas time.
"We are deeply saddened that our beloved father passed away today," Professor Hawking's children, Lucy, Robert, and Tim said in a statement.
"He was a great scientist and an extraordinary man whose work and legacy will live on for many years."
‘An inspiration'
Prime Minister Theresa May was among the first to pay tribute, writing on Twitter that Hawking was "a brilliant and extraordinary mind" whose legacy "will not be forgotten".
Well-wishers lined up at the University of Cambridge to sign a book of condolences.
"He was a fun person to work with and had a great sense of humor. For his students, at the blackboard, sometimes a little scary... He was an inspiration," Justin Hayward, who was Hawking's Ph.D. student from 1991 to 1995, told AFP.
Hawking defied predictions that he would only live for a few years after developing a form of motor neurone disease in his early 20s.
The illness gradually robbed him of mobility, leaving him confined to a wheelchair, almost completely paralysed and unable to speak except through his trademark voice synthesiser.
"His courage and persistence with his brilliance and humor inspired people across the world," his family said.
"He once said, 'It would not be much of a universe if it wasn't home to the people you love'. We will miss him forever."
A titan of science
Born on January 8, 1942 — 300 years to the day after the death of the father of modern science, Galileo Galilei — Stephen William Hawking became one of the world's most well-regarded scientists and entered the pantheon of science titans.
His death was announced on the 139th anniversary of the birth of Albert Einstein.
Hawking had an enduring fascination with the mysteries of black holes.
His work focused on bringing together relativity — the nature of space and time — and quantum theory — how the smallest particles behave — to explain the creation of the universe and how it is governed.
"My goal is simple," he once said. "It is complete understanding of the universe, why it is as it is and why it exists at all."
But he was also a beloved figure in popular culture, with cameos in "Star Trek: The Next Generation" and "The Simpsons." His voice appeared in Pink Floyd songs.
Tributes poured in from scientists around the world.
American astrophysicist Neil deGrasse Tyson tweeted his condolences, with a characteristically cosmological reference.
"His passing has left an intellectual vacuum in his wake. But it's not empty. Think of it as a kind of vacuum energy permeating the fabric of spacetime that defies measure," the scientist said.
NASA issued its own Twitter eulogy, publishing a video of the scientist grinning as he soared into weightlessness on a zero gravity flight at the Kennedy Space Center in Florida, escaping his wheelchair for a brief period.
His international reach was demonstrated in China, where news of his death generated nearly half a billion clicks as fans
bade farewell on social media platform Weibo to a "giant star.”
'End of the human race'
Hawking's first marriage to Jane Wilde in 1965 gave him three children and was immortalised in the 2014 film "The Theory of Everything."
Eddie Redmayne, who won an Oscar for his lead role in the film, said: "We have lost a truly beautiful mind, an astonishing scientist and the funniest man I have ever had the pleasure to meet."
The couple split after 25 years and Hawking married his former nurse, Elaine Mason, but the union broke down amid allegations that he was being abused. He refused to comment.
Hawking became one of the youngest fellows of Britain's most prestigious scientific body, the Royal Society, at the age of 32.
In 1979 he was appointed Lucasian Professor of Mathematics at Cambridge University — a post previously held by Newton.
Hawking was an outspoken commentator on life back on earth, voicing his disapproval in recent years of both the election of Donald Trump in the United States, and Britain's vote to leave the European Union.
He also commented on the future of technology, warning that "the development of full artificial intelligence could spell the end of the human race."
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