The group, RevolutionMuslim.com, has warned the cartoon's creators, Trey Parker and Matt Stone, that they could face violent retribution.
The group's site, which is currently down, featured a post directed at Parker and Stone claiming they "outright insulted" the religious leader.
The post showed a gruesome picture of, a Dutch filmmaker who was shot and stabbed to death in an Amsterdam street in 2004 by a fanatic angered by Van Gogh's film about Muslim women. The film was written by a Muslim woman who rejected the Prophet Muhammad as a guide for today's morality.
"We have to warn Matt and Trey that what they are doing is stupid and they will probably wind up like Theo Van Gogh for airing this show," the post read. "This is not a threat, but a warning of the reality of what will likely happen to them."
The post listed the addresses of Comedy Central's New York office and Parker and Stone's California production office.
CNN said the New York-based website is known for posts in support of Osama bin Laden and jihad, or holy war, against the West.
The post's author, Abu Talhah Al-Amrikee, told The Associated Press in a phone interview Wednesday that the article was written to raise awareness of the issue and to see that it does not happen again. Asked if Parker and Stone should feel threatened by it, he said "they should feel threatened by what they did."
The 200th episode for the cheeky and vulgar cartoon was intended to feature many of the personalities and groups that Parker and Stone insulted during the series' run.
In 2006, Comedy Central banned the men from showing an image of Muhammad on their show. They had intended to comment on the controversy created by a Danish newspaper's publishing of caricatures of the Islamic leader.
Muslims consider any physical representation of their prophet to be blasphemous.
Comedy Central and the show's producers would not comment.