Khan, who fought a long battle with cancer, carved out a stellar career in Bollywood, Hollywood and other Western films.
Acclaimed Indian actor Irrfan Khan, whose international movie career included hits such as Slumdog Millionaire, Life of Pi and The Amazing Spider-Man, has died aged 53, his publicist said.
Khan, who was diagnosed with a neuroendocrine tumour in 2018, died on Wednesday after he was admitted in a Mumbai hospital for colon infection. He was 53.
"Irrfan was a strong soul, someone who fought till the very end and always inspired everyone who came close to him," his publicist said in a statement.
He spent his final hours "surrounded by his love, his family for whom he most cared about," a statement released by his family said.
The actor had spent several months last year in the United Kingdom undergoing cancer treatment.
His mother Saeeda Begum died four days ago on April 25.
He is survived by his wife, TV producer Sutapa Sikdar, and sons Babil and Ayan.
One of the best crossover actors
Born Sahabzade Irfan Ali Khan in the Indian desert state of Rajasthan on January 7, 1967, Khan discovered an early passion for acting and studied at the elite National School of Drama.
But his training in Shakespeare and Chekhov did little to ease his entry into the Hindi film industry, which was largely focused at the time on churning out formulaic song-and-dance blockbusters.
Even as he landed a role in 1988's Salaam Bombay - directed by first-timer Mira Nair - his part was slashed to a cameo.
He sobbed for hours when he found out about the cuts, he told India's Open magazine. "It changed something within me. I was prepared for anything after that," he said.
Television roles followed, along with a handful of bit parts in Bollywood, where producers routinely dismissed him as looking too unconventional to play the lead.
By the time British director Asif Kapadia cast him as a mercenary in The Warrior, he was ready to quit acting, frustrated over the direction of his career.
But, in a sign of the global success that lay in wait, the 2001 film racked up awards and won Khan praise - including in India, where a new generation of directors was eager to experiment with fresh story lines.
His drama school training came in handy when he was cast in Maqbool and Haider - contemporary Hindi adaptations of Macbeth and Hamlet.
But he also charmed audiences in lighter fare such as Piku, featuring Bollywood superstars Amitabh Bachchan and Deepika Padukone, and The Lunchbox, in which he played a lonely accountant in love with a housewife.
'An incredible talent'
The tall and lanky actor won India's national award for his performance in Paan Singh Tomar. He was also awarded with Padma Shri, one of the country's highest civilian honors.
Khan was among the first Indian actors to make a consistent mark in Western cinema, following earlier crossover pioneers like Saeed Jaffrey, Roshan Seth and Om Puri.
He featured in several award-winning international films such as The Warrior, Slumdog Millionaire and Life of Pi. In Hollywood, he worked in The Amazing Spider-Man, Inferno and Jurassic World.
Khan consciously sidestepped traditional Bollywood tropes, focusing on the subtleties of his craft.
This allowed him to carve out a stellar career in Hollywood as well, where he collaborated with Oscar-winning directors such as Danny Boyle and Ang Lee and appeared in the HBO show In Treatment.
The actor was last seen in Bollywood comedy, Angrezi Medium, which was released in March.
"An incredible talent," said Amitabh Bachchan in one of many Twitter tributes.
"A gracious colleague. A prolific contributor to the world of cinema... left us too soon creating a huge vacuum," said the veteran actor.
Filmmaker Karan Johar said, "Thank you for raising the bar as an artist ... Thank you for enriching our cinema... We will miss you terribly, Irrfan."
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