John Nash, 86, and his 82-year-old wife Alicia were killed when their taxi crashed in New Jersey, police say.
The mathematician is renowned for his work in game theory, winning the Nobel Prize for Economics in 1994.
John Nash’s breakthroughs in mathematics and and his struggles with schizophrenia were the focus of the 2001 A Beautiful Mind.
Russell Crowe, who played John Nash in the movie, tweeted: “Stunned… My heart goes out to John & Alicia & family. An amazing partnership. Beautiful minds, beautiful hearts.”
Director Ron Howard, also tweeted his tribute to the “brilliant” John Nash and his “remarkable” wife.
Alicia Nash helped care for her husband, and the two later became prominent mental health advocates.
John Nash and Alicia Nash were thrown from their vehicle, police said. Media reports said the couple may not have been wearing seatbelts when they crashed.
Their taxi driver, and a passenger in another car, were also injured.
Born in Bluefield, West Virginia, John Nash first studied in Pittsburgh before moving to Princeton.
His recommendation letter contained just one line: “This man is a genius.”
John Nash married Alicia Larde in 1957, after publishing some of his breakthrough works.
He developed severe schizophrenia soon after, and Alicia had him committed for psychiatric care several times. The couple divorced in 1962.
John Nash said in an interview on the Nobel website: “I was disturbed in this way for a very long period of time, like 25 years.”
However, they stayed close, and John Nash’s condition had begun to improve by the 1980s. They remarried in 2001.
This week John Nash received the Abel Prize, another top honor in the field of mathematics.
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