Frank Detorre (Bill Murray) is an unkempt, slovenly zookeeper at the Sucat Memorial Zoo in Rhode Island. Depressed by the loss of his wife Maggie years earlier, he copes by eating unhealthily and ignores basic hygiene, to the annoyance of his young daughter Shane (Elena Franklin). During a lunch break, Frank eats a boiled egg he dropped onto the ground after a chimpanzee had stolen it and put it in its mouth. Inside Frank's body, Osmosis "Ozzy" Jones (Chris Rock), a rebellious and disgraced white blood cell officer of the Frank PD, recklessly chases germs from the egg, but fails to catch them and instead causes Frank to have a bad leg cramp. Meanwhile, facing a serious challenge to his re-election prospects, Mayor Phlegmming (William Shatner) doubles down on Frank's consumption of junk-food, despite concerns from his secretary Leah Estrogen (Brandy). Meanwhile, Thrax (Laurence Fishburne), a deadly red virus, emerges from the leftover egg and sadistically causes inflammation in the throat. Unwilling to admit responsibility for the recent symptoms, Phlegmming instructs Frank to take a cold pill through brain signals. The suppressant, Drixenol "Drix" Koldreliff (David Hyde Pierce), is partnered with Ozzy to investigate the recent sore throat. While Drix cools off the inflammation, Ozzy gets a short eyewitness testimony from a terrified bacterium who saw Thrax arrive. Thrax assumes leadership of a gang of sweat germs and launches an attack on the mucus dam in Frank's nose, causing a runny nose, nearly expelling Ozzy and Drix before Frank inhales them back into the sinuses. While continuing the investigation, Drix hears that Phlegmming remembers Ozzy setting the worst record in Frank's body and he doesn't want him to do the same thing when Frank planned a trip to the wing festival in Buffalo, New York. When he wonders aloud why Ozzy had a record, Ozzy reveals to Drix that two years ago, during a science fair at Shane's school, he caused Frank to publicly vomit on Shane's science and P.E. teacher, Mrs. Boyd (Molly Shannon), after seeing a deadly virus on an oyster Frank ate earlier after observing Zack's oyster display thanks to a boy telling people to look at Frank. The story ran in the newspaper the next day, resulting in Frank, Shane, Mrs. Boyd, and even their whole families becoming the town laughingstocks overnight causing them to be humiliated every year as well as Frank being fired from his job at the pea soup factory by his manager and supervisor after he embarrassed them. His brother and Shane's uncle Bob (Chris Elliott) later helped him get a job at the zoo, where Frank still gets zero respect. Ozzy, in turn, was then suspended from his job working in the kidneys and then demoted to patrol duty in the mouth for excessive use of unnecessary force. Ozzy tells Drix how he wonders every day if what he did was right since then. Drix, in turn, assures Ozzy that he did the right thing as raw oysters are frequently breeding grounds for potentially dangerous bacteria which is what Ozzy was trying to tell everybody. Based on information from a vaccine virus, Ozzy and Drix go undercover at a nightclub located within a large zit on Frank's forehead, intending to infiltrate Thrax's gang. Once there, the two discover Thrax's plan to steal chromosomes from the hypothalamus, driving up Frank's body temperature and killing him in 48 hours. However, Ozzy's cover is blown and he is forced to scream for help from Drix, who destroys the club with a grenade. The explosion bursts the zit during Frank's meeting with Mrs. Boyd, causing it to land on her lip, grossing her out, and she angrily screams at him to leave. In response, a furious Phlegmming closes the investigation, fires Ozzy, and orders Drix to leave the city. Having survived the assault, Thrax kills his last surviving gang members, then discreetly breaks into the hypothalamus gland and steals a DNA bead from a chromosome. Frank's body temperature begins to rise. Ozzy, realizing that Thrax was still a threat, stops Drix from leaving and convinces him to come back and help him finish the case. Thrax then kidnaps Leah and flees to the uvula to escape. When Phlegmming attempts to speak with Bob, But it is useless, He began to scream in fear. As Frank is taken to the hospital in a fever induced coma, Ozzy and Drix give chase and save Leah but Thrax escapes out of the mouth by using pollen, causing Frank to sneeze and expelling Thrax from his body. With Drix's help, Ozzy pursues Thrax to the surface of Shane's right eye and her false eyelash. Thrax pins Ozzy down and threatens to kill Shane next, but gets stuck in the eyelash; Ozzy's pliable body allows him to escape and hang onto Shane's real eyelash as the false eyelash slides off and lands in a glass of rubbing alcohol, dissolving a screaming Thrax to death. As Frank's temperature reaches 108 degrees, his heartbeat flatlines as he suffers hyperpyrexia, leaving Shane devastated. Riding on one of Shane's tears, Ozzy reenters Frank's body with Thrax's necklace of DNA beads, reviving Frank just in time. Having narrowly cheated death, Frank commits himself to living a much healthier lifestyle with the help of Shane, while Ozzy begins a relationship with Leah and is re-instated to the force with Drix as his new partner. Phlegmming loses his position as mayor and is reduced to working as a custodian in the bowels. He later accidentally ejects himself from the body by pushing a button that triggers Frank's flatulence.
