Welsh-born Hopkins, who won an Oscar in 1992 for his role as the flesh-eating Dr Hannibal Lecter, will take on the papal role in the forthcoming movie, Edgardo Mortara.
It is based on the true story of a young Jewish boy who was kidnapped by the Vatican in the mid-19th century after being baptised by his nanny.
Hopkins, from Port Talbot, south Wales, plays Pope Pius IX, who risked international criticism for refusing to give up the little boy.
The boy's father, who tries desperately to win back his son, will be played by Spanish actor Javier Bardem who was nominated for an Oscar for his role in Before Night Falls.
The film, developed by Channel 4 offshoot FilmFour, is due to start shooting in Italy later this year.
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It will be directed by Damien O'Donnell who was behind the hit British film East Is East.
Hannibal Lecter was Hopkins' most famous role. The flesh-eating doctor from The Silence of the Lambs and Hannibal was so popular with movie-lovers, he was voted the "best baddie" in cinema history.
Dr Lecter even beat the Star Wars villain Darth Vadar, and Norman Bates, the killer from classic thriller Psycho.
Hopkins won a best actor Oscar for his portrayal of the serial killer in Dr Lecter's first screen outing, The Silence of the Lambs, in 1992.
The film, which also starred Jodie Foster, picked up another four Oscars and its suspense has become embedded in cinema history.
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