While the Hollywood star of films like "Pirates of the Caribbean" and "Finding Neverland" will be playing the central role in the film, Amitabh will be the kind-hearted Mumbai gangster.
The New York based Indian filmmaker, who was approached by Depp to direct "Shantaram", couldn't have asked for a better deal.
"It was an honour for me that Depp asked me to make the film. It will go on the floors in November. But right now I busy with the release of my 'Namesake' in India," says Nair told.
When asked about other members of the cast, Nair said it was just Depp and Amitabh right now.
The "Monsoon Wedding" director describes herself as a very intuitive person and one who selects her projects on the basis of her instincts.
And "Shantaram", which will be extensively shot in Australia, China and India, is a story with true global appeal, she said.
"Shantaram" is a screen adaptation of Gregory David Roberts' book of the same name. The film will show how Roberts (played by Depp), a convicted Australian bank robber and heroin addict, escapes from Pentridge Prison, Australia, and flees to India to make his base in Mumbai.
In Mumbai, Roberts has to deal with the Mumbai mafia. He later decides to help slum dwellers and starts a health centre that provides free medical facilities to the poor. It is here that Roberts befriends Kader Bhai (Amitabh) who eventually becomes his mentor and guide.
This is not Nair's first stint with a Hollywood actor.
She had earlier teamed up with Hollywood biggies Denzel Washington in "Mississippi Masala" and Reese Witherspoon in "Vanity Fair".
Asked about her views on Bollywood and the chances of her making a typical potboiler, she said: "I am all for commerciality. I love Bollywood formula but other people make better than me. I make my own kind of cinema, which is very commercial.
" 'Monsoon Wedding' is probably the most successful commercial Hindi film in the world at the moment. In a way it's made more money than all these films."