Angry celebrities and violent ginger kids are after the "goo" of the Islamic prophet Muhammad in order to become immune to slander. To add to the mess, the celebrities activate Mecha-Streisand and threaten to destroy South Park. Despite this, the mystery of “Who is Eric Cartman’s father?” obsesses Cartman.
The episode begins with a flashback of Mitch Conner in the Vietnam War, then it goes to the present time. Where Cartman is questioning Mr. Garrison and Mr. Hat about his father's true identity, Mr. Garrison refuses to tell, so Cartman decides to go to Dr. Mephesto instead.
Meanwhile, the Gingers demand to see if the person in the teddy bear costume is really Muhammad, so they unzip the costume to reveal it is actually Santa Claus. Stan tells them they made a promise to Jesus that Muhammad would stay in the U-haul, but before they could do anything, Mecha-Streisand appears and starts destroying South Park. Meanwhile, the Super Best Friends are trying to come up with a way to destroy Mecha-Streisand, while Buddha is still snorting cocaine and Jesus is watching pornography, after she rages through the town and destroys many buildings along with several residents from the series' history. They decide to help get on the Super Best Friends Power Cycles, which are Segways. Cartman shows up at Dr. Mephesto with Mitch Conner disguised as a stereotypical African American man trying to get into Dr. Mephesto's lab. Mecha-Streisand continues destroying South Park, squashing and killing Pip while he attempts to reason with her. Stan, Kyle, and Kenny immediately go to Mephesto's lab after coming up with an idea to clone Muhammad so that all that the gingers and the celebrities receive the power never to be offended again, however Cartman still demands to know who is father is but they clone Muhammad first. Then Cartman and Kyle get into a debate about which is more important, Cartman's Father or Muhammad? The gingers end up capturing Muhammad, the boys, and Dr. Mephesto, while Cartman is in a tunnel and then sees that Scott Tenorman is back.
The Super Best Friends pacify Mecha-Streisand by having Krishna adopt the form of Neil Diamond and providing her the opportunity to perform a duet with him.
The celebrities get Muhammad first, and Tom Cruise finally becomes able to never be insulted again. But the gingers then surround the entire town until they get Muhammad too, while Cartman confronts Scott Tenorman (who first appeared in "Scott Tenorman Must Die") once again, where it is revealed that Scott was in a mental institution for several months while finding out all of the information about Cartman. Scott then forces the town's residents to tell Cartman that his father was one of the Denver Broncos. Scott also reveals that his own father was a Denver Bronco who had an affair with Cartman's mother, making them half-brothers. It also ironically means that Cartman had his own father killed and fed him to Scott. So Scott forces Cartman to eat chilli, but the Super Best Friends break in and free Cartman and fight the celebrities and gingers, while Stan unintentionally mocks on Tom Cruise once again when Seaman jumps on his back, revealing he could still be mocked on. Scott Tenorman escapes on a jetpack promising the Super Best Friends he'll be back. much to Jesus' confusion. Tom asks Rob Reiner how he could still be made fun of if he had Muhammad's goo. Kyle says that there is no goo. He starts to give the traditional 'I learned something today' speech, which (obviously referencing Comedy Central being threatened by extremists over their previous portrayal of Muhammad) states that the goo has no power and that, based on experience, fear, intimidation, and violence are the only ways that work. Everyone agrees (this entire speech was censored by Comedy Central and not as an in-joke by the creators, given that it was done without their input).
The town works on re-building itself once again, and Cartman is crying over his father, but instead of grieving that he had him killed, he is sad that he is a half-ginger, Mitch cheers him up by saying that he's also half Denver Bronco which makes Cartman stop crying, after that Mitch Connor goes away. Tom Cruise cries and wishes he could never be mocked on again. Taking pity on him, the boys sincerely tell Tom of a place where he would never be offended or hurt again, offering him a way to get there as well (never having learned that they were mislead before). The final scene is on the Moon, where Cruise's dead body is seen next to the dead whale from "Free Willzyx".
The A.V Club writer Sean O'Neal had stated that this episode was an improvement of the previous episode, but nevertheless felt "201" was less a cohesive episode than a grab bag of balls-out crazy scenes and cameos only loyal fans would really appreciate". However, he also stated "it's sure to become one of, if not the most talked-about episode of South Park ever". Ramsey Isler of IGN stated that the episode was built on the event of "200" and delivered a strong payoff, particularly with the subplot revolving around Eric Cartman's father and the way it tied back to "Scott Tenorman Must Die".