The Mad Lib Theater game featured Fallon asking Portman to fill out a Mad Libs-inspired questionnaire -- answering "Kim Kardashian" for a celebrity and "you suck at Fortnite" for a childish insult -- and then acting out a scene where her answers filled in gaps in the dialogue.
"Is this because of my slimy knees?" Fallon's character asked during the scene.
"No, we're just two different people," Portman's character responded. "I was brought up by two scuba divers, and you were raised by llamas."
Portman earlier told Fallon the Comic-Con announcement of her upcoming turn as the female version of Thor in Thor: Love and Thunder was "nerve-wracking."
"I was afraid someone was going to call me out for something," she told the host.
Portman said she was surprised by the heft of the hammer she walked out holding during he announcement.
The actress said her new movie, Lucy in the Sky, deals with "an astronaut who has a hard time coming back from space."
The film is inspired by the real-life case of Lisa Nowak, who pleaded guilty to charges of felony burglary of a car and misdemeanor battery following a 2007 incident where she stalked her former lover's new girlfriend.
Portman told UPI in a recent interview that she was attracted to how the film treated her character, Lucy Cola, differently than female astronauts in other movies.
"A lot of times, when it's a female astronaut, they give her a child back on Earth and that's the drama," Portman said. "Like the only drama that a woman could possibly have would be thinking about her child while she's away. So to have a woman whose main emotional drama is having an existential crisis I thought was kind of radical."