Producers plan to re-cast the role in the coming months.
Milhouse van Houten has been a popular recurring character on the sitcom for the past 35 years, and is Bart Simpson’s best friend.
He is shy in nature, easily influenced by Bart’s mischievous ideas, and regularly targeted by bullies.
Milhouse is not the only character played by Hayden. She is also the voice behind Ned Flanders’ sons Rod and Todd, school bully Jimbo Jones, Lisa Simpson’s friend Janey, and Chief Wiggum’s wife Sarah.
But Milhouse was her most popular character, Hayden said, recalling in a video announcing her departure, external that “people would come up to me and they quote Milhouse lines”.
“People are always saying what a nerd he is, but one thing that I love about Milhouse is he’s always getting knocked down, but he keeps getting up,” she continued. “I love the little guy. It’s this wonderful analogy for life.”
The show’s creator Matt Groening said: “Pamela gave us tons of laughs with Milhouse, the hapless kid with the biggest nose in Springfield. She made Milhouse hilarious and real, and we will miss her.”
The blue-haired boy was said to be named after former US president Richard Milhous Nixon.