Sometime after they helped destroy Evil Bong, Eebee, college student Larnell finds Alister McDowell at his dorm room door, remarking “I almost didn’t recognize you” (a reference to Alister's recasting). Larnell invites him in and explains something is wrong with him and his roommates Bachman, and Brett: Bachman has become narcoleptic followed by amnesia, Larnell has uncontrollable sexual urges, and Brett has become massively overweight due to an uncontrollable appetite.
The group decides to call the delivery man Rabbit, who first delivered Eebee. He arrives and after a brief interaction with Larnell, agrees to trade information for marijuana. He tells them Jimbo Leary bought the bong in the Amazon in the 1960s' while working for the peace corps. When half his friends die after smoking from Eebee, Jimbo locked her in his attic where she stayed until his wife sold it, leading to the events of the first film. Believing they can find a cure, the five men travel to the Amazon. There, they encounter Velicity, a woman who's continuing her recently-deceased-father's research with his research partner. Larnell and Rabbit discover a pile of marijuana behind Velicity's hut, packed to move. Guarding it is Velicity's partner, Larnell's grandfather Cyril, who's inexplicably out of his wheelchair and able to walk. Larnell and Rabbit go inside the hut where Velicity explains that her father uncovered a prehistoric strain of marijuana cultivated by an ancient people, "the Poontang Tribe". She's found that the marijuana can be used to help cure people of health problems and severe injuries-explaining how Cyril is able to walk again-and Velicity is planning on donating the marijuana to help cancer patients. Bachman suggests that the marijuana could help them with their extreme side effects, so they smoke some and it seems to work.
Larnell pulls out leftover pieces of Eebee's face which Velicity immediately recognizes as Poontang craftsmanship. Eebee is brought back to life by the ancient marijuana smoke and Velicity takes the pieces to Cyril. She overhears a phone call between Cyril and a potential buyer, so she confronts him. He chastises her for her naivety and she runs off upset. Having heard Cyril's plan, Eebee offers her help if he helps restore her original form, which Cyril does. Rabbit shows up and tries to cut a distribution deal with Cyril, threatening to expose Cyril's intended operation if he doesn't cut him in, when three Poontang Tribeswomen appear behind them, holding spears. They attack Cyril (who runs off) and capture Rabbit and Eebee. The three women bring Rabbit and Eebee to King Bong even larger, skull-shaped bong with eyes. They place Eebee on an altar next to King Bong and they argue, revealing a past relationship. The women “force” Rabbit to smoke from the King Bong and he enters the Bong World. Cyril returns to the hut, bleeding, where he tells the others what happened. Larnell, Velicity, Alister, Bachman and Brett head out to save Rabbit leaving Cyril behind.
They find King Bong and theorize that he's more powerful than Eebee and has ability to pull a person's whole being into the Bong World, not just their soul. Eebee, still being bitter from King Bong's implied infidelity, tells them they have to destroy his “symbol”, a necklace and the source of his power. Bachman and Brett enter the Bong World (this time a jungle) and are danced on by two mostly nude tribeswomen before being tied up and brought before King Bong with Rabbit. Larnell and Alister enter find the tribe rolling Rabbit up in giant paper, turning him into a massive joint that King Bong shrinks down to a normal size with his necklace. They untie Bachman and Brett and the group attacks the tribe while Larnell shatters the necklace, destroying King Bong and sending them out of the Bong World. They all walk off, ignoring Eebee's angry cries to them not to leave her on the altar alone. The film ends with everyone smoking in Larnell's dorm, everything back to normal.
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