The 41-year-old actress and 47-year-old actor play Wren and Miguel, two doctors who fall in love while working in war-torn West Africa.
"It was a script that I was familiar with for a very long time. When I read it again, imagining [Charlize] in it, it took a very big turn in terms of what I thought would [be] the overall tone of the film," Penn told reporters at the 2016 Cannes International Film Festival.
"It had not been something I considered doing previously ... in particular, Charlize with Javier," he added. "I don't want to talk too much about that because I feel so strongly that it's in the film and I want people to see that. I'm just a fan of great performances, and that's what they are."
Theron and Penn dated over a year before splitting in summer 2015. The actress subsequently discussed The Last Face in the May issue of British GQ, calling the collaboration "a beautiful film."
"We both care enough about each other to know we care about this movie together," she said. "Do I wish people would respect that and look at the film for what it is? Of course I do, but I know I'm not God and that's probably not going to happen."