Mankell, who first revealed he had cancer in January last year, "died in his sleep early this morning" in Sweden's second city of Gothenburg, his publisher Leopard said on its website.
Mankell's collection of dark novels about the Swedish police inspector Wallander brought the author international fame after it was made into a television series by the BBC starring Oscar-nominated actor and director Kenneth Branagh.
"Henning Mankell was one of the great Swedish authors of our time, loved by readers in Sweden and all over the world," said a statement from Leopard, which Mankell co-founded in 2001.
Mankell, who shared his time between Sweden and Mozambique, published more than 40 novels, plays and children's books, selling around 40 million copies around the world.
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The Wallander series itself won numerous awards and contributed to the massive global interest in Scandinavian crime and thriller novels dubbed Nordic noir.
Mankell first revealed he had cancer in a newspaper column in January 2014, saying it was discovered when he underwent treatment for a slipped disc.
"A few days later... I had it in black and white: it was serious. I had one tumour in the back of my neck and one in my left lung. The cancer could also have spread to other parts of my body," he wrote at the time.
Mankell was also known for rights activisim, and joined a flotilla in 2010 trying to break the Israeli blockade and take aid to the Gaza Strip.
He said he wanted to create a situation where "Palestinians are not treated like second-class citizens in their own country, a sort of apartheid system."
In Mozambique, he was artistic director of the Teatro Avenida theatre group.
Mankell leaves a widow Eva Bergman, 70, the daughter of Swedish cinema great Ingmar Bergman, and his son Jon.