The news follows the Spanish actor's recent collaboration with Penn on The Gunman.
According to Hollywood blog Deadline, The Last Face will include Charlize Theron - Penn's current romantic interest, and France's Adele Exarchopoulos, star of Blue is the Warmest Colour.
The film will be shot in Africa with the project set to get the green light from the production company River Road.
Theron will play a doctor who lives in Africa doing humanitarian work while trying to endure the political conflicts that wrack the country.
Bardem will also play play a doctor in a similar situation, according to Deadline.
Exarchopoulos' role will be a journalist who tracks the lives of the leading characters.
Bill Pohlad (12 Years a Slave) will lead the production team. Penn and he previously worked together on Into the Wild, Tree Of Life and Fair Game.
The original screenplay was written by Erin Dingam, who had a bit part in The Crossing Guard, Penn's second work as a director after debuting with The Indian Runner in 1991.
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