The 49-year-old actress took instructions from Ellen DeGeneres via an earpiece for the hidden camera prank at a dry cleaners in Burbank, Calif.
McCarthy pretended to be sedated as she dropped off clothes at a dry cleaners. She told an employee she accidentally took Tylenol PM instead of Tylenol and drank sleepy time tea instead of green tea.
"I'm having a day," McCarthy says.
DeGeneres then had McCarthy offer a number of suggestions for the sign outside the dry cleaning business.
"Give a man a clean shirt and he'll press it for a day. Teach a man to clean a shirt and we'll hire him," McCarthy says.
"Fool me once, shame on you. Fool me twice, shame on you for fooling me. And shame on you," she later adds.
McCarthy then pretended to fall asleep and fell to the floor before coming clean about the prank.
DeGeneres had pranked McCarthy during the actress' last visit to the show by having singer Billie Eilish pop out and scare her. McCarthy said in her interview with DeGeneres that she "panicked" in the moment.
"I think the last time I was on is what I like to consider my first heart attack," she said. "I watched it back and I don't think I look as crazy as I felt, because I was so panicked. I was like, 'I'm going out.'"
McCarthy last starred in the film The Kitchen, which opened in theaters in August. She will star in and produce the upcoming movie Super Intelligence, which is directed and co-produced by her husband, Ben Falcone.