Mark Ruffalo had a lot of doubts about his performance during the shoot. He often half-joked that his friend Oscar Isaac, who was filming on a nearby sound stage, was going to be called in to replace him. One day, Willem Dafoe pranked Ruffalo by taking him to a room where Isaac (who was in on the joke) was waiting. Isaac and Dafoe informed Ruffalo he was fired and, indeed, getting replaced by Isaac.
Willem Dafoe described the makeup process, "Four hours in, two hours out every day - I'm showing up at three o'clock in the morning, sitting in the chair, meditating and trying to deal with standing still. You can't sleep because it's intricate enough that you've got to work with the people applying it. It's a grind, but I liked working with a mask in there - quite literally, a mask."
Director Yorgos Lanthimos wanted to evoke an Old Hollywood feel by using painted sets. Most of the film was shot on soundstage, but the ballroom scene was shot on location.
Mark Ruffalo initially was hesitant about the role of Duncan Wedderburn after first reading the "Poor Things" script, penned by Tony McNamara. "I said to [director, Yorgos Lanthimos], 'I don't think I'm right for this'," Ruffalo said. "And he just laughed at me and he's like, 'It's you.'"