The Oscar-nominated star passed away at his home in Kentucky on Thursday night.
A spokesman for the Shepard family revealed the cause of death was complications of amyotrophic lateral sclerosis, or Lou Gehrig’s disease.
Shepard's career saw him win equal acclaim as an actor, playwright and director; earning a Pulitzer Prize for his 1979 play Buried Child in 1979, while he went on to land an Academy Award nomination for Best Supporting Actor in his role as pilot Chuck Yeager in 1983's The Right Stuff.
During his trail-blazing career in showbusiness, Shepard penned 44 plays as well as several books of short stories and was once hailed by New York as "the greatest American playwright of his generation".
Sam Shepard dies at 73
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He recently starred in the hit Netflix thriller Bloodline as the head of a tortured family, Robert Raybun. His final film, titled Never Here, was released to stellar reviews in June this year.
Shepard was surrounded by his children and sisters when he died after battling with ALS for some years.
He leaves children Jesse, Hannah and Walker Shepard and sisters Sandy and Roxanne Rogers.
A downpour of stars paid tribute to the actor, with many describing Shepard as a "hero".
Game of Thrones actor Nikolaj Coster-Waldau posted on Twitter?: "A hero of theatre. A hero of writing. A hero of acting. A hero of mine. Sam Shepard RIP."
Sam Shepard starred as Robert Raybun in Bloodline
Shepard won the 1979 Pulitzer Prize for his play Buried Child
While Star Trek star George Takei enthused: "Sam Shepard was a towering figure in American theater and film. He indeed had 'the right stuff.' His voice will truly be missed."
British playwright Jack Thorne tweeted: "Sam Shepard was a beautifully savage writer who seemed to see an America (and, indeed, a world) others did not. He will be deeply missed."
House of Cards showrunner Beau Willimon said: "Sam Shepard is one of the greats. These eyes saw so much, and he wrote of what he saw with fearless, timeless honesty. RIP maestro."
Sam Shepard and Jessica Lange dated from 1982 to 2009 but never married
Seinfeld's Jason Alexander wrote: "A great man of the theater has passed. Thank you, Sam Shepard. RIP."
Jessica Lange, who dated Shepard from 1982 to 2009, opened up about her relationship with the actor in a recent interview just days before his death.
"I wouldn’t call Sammy easygoing and funny, but everybody has their dark side, and he always does it with a sense of humour," the 68-year-old American Horror Story star told AARP magazine.