Hayes, who has played the ladies' man/school cook in the animated Comedy Central satire since 1997, said in a statement Monday that he feels a line has been crossed.
"There is a place in this world for satire, but there is a time when satire ends and intolerance and bigotry towards religious beliefs of others begins," the 63-year-old soul singer and outspoken Scientologist said.
"Religious beliefs are sacred to people, and at all times should be respected and honored," he continued. "As a civil rights activist of the past 40 years, I cannot support a show that disrespects those beliefs and practices."
"South Park" co-creator Matt Stone responded sharply in an interview with The Associated Press Monday, saying, "This is 100 percent having to do with his faith of Scientology... He has no problem — and he's cashed plenty of checks — with our show making fun of Christians."
Last November, "South Park" targeted the Church of Scientology and its celebrity followers, including actors Tom Cruise and John Travolta, in a top-rated episode called "Trapped in the Closet." In the episode, Stan, one of the show's four mischievous fourth graders, is hailed as a reluctant savior by Scientology leaders, while a cartoon Cruise locks himself in a closet and won't come out.
Stone told The AP he and co-creator Trey Parker "never heard a peep out of Isaac in any way until we did Scientology. He wants a different standard for religions other than his own, and to me, that is where intolerance and bigotry begin."