The Oscar winning star of Chicago is to play the Egyptian queen in the upcoming $30 million 3D Hollywood epic Cleo.
Hugh Jackman, the Australian actor who starred in the X Men, is in talks to play her Roman lover Mark Antony.
The film, which is Hollywood's first attempt at a musical based on the life of two of history's most famous lovers, will be directed by Steven Soderbergh, who made his debut with Sex, Lies and Videotapes, and will feature a soundtrack by the punk band Guided by Voices.
Zeta-Jones, 39, astounded fans and critics when she revealed her musical skills in the Oscar winning 2002 big screen adaptation of Chicago.
The Welsh born actress, who co-starred in the musical film opposite Richard Gere and Renee Zellweger, won the best supporting actress Oscar for her performance as the gun-toting Velma Kelly.
The definitive film of Cleopatra's life remains the 1963 version starring Elizabeth Taylor and Richard Burton.