A gifted and smart young man tries to navigate life, puberty, and love while trying to survive his often dimwitted, dysfunctional family.
When Dewey's pet rabbit does good in a state contest, the family must travel to Las Vegas for the nationals. But Reese unknowingly sells the rabbit to a restaurant. Now it is up to Dewey (with a little help from a "choking" Reese) to try and save the rabbit. Meanwhile, Malcolm tells Hal and Lois that they embarras him, and that is why he didn't tell them he won state science honors. As a form of repayment, Malcolm gets great seats for him and Lois to see Lois' favorite singer. Lois then gets lucky and is invited backstage where all she really wants to do is figure out why Malcolm doesn't want her around. Hal, on the other hand, is looking all across Las Vegas for a slot machine that he has had dreams of winning the jackpot on. Francis is also in trouble when he gets behind on duties at the ranch, and for the first time sees that Otto isn't just a pushover for everything.
Hal and the boys offer to watch baby Jamie so an exhausted Lois can finally get some sleep. Hal leaves the boys in charge while he goes to the Lucky Aid to pick up more diapers. While the boys are watching Jamie, three beautiful teenage girls arrive and woo Malcolm, Reese and Stevie away for the night, leaving Dewey alone with the baby. Meanwhile at the Lucky Aid, Hal doesn't have enough money for the diapers and Craig forces him to work. Back at home, Dewey concocts an elaborate bedtime story for Jamie involving each member of his family.
No one wants to tell Stevie his parents are getting a divorce, until Reese spills the beans.
Malcolm skips out on Thanksgiving to go to a party; Reese becomes abusive to Hal and Dewey as he attempts to prepare Thanksgiving dinner.
Malcolm chooses Reese as his subject for an Abnormal Psychology mid-term project; Dewey earns some extra cash as a street performer.
Malcolm gets a job working for Lois on the drugstore loading dock but is shocked to find that Lois smokes. She makes him promise not to tell, then turns her back on him and writes him up for a silly offense. Meanwhile, Dewey runs away to the Ranch to be with Francis because he says he is tired of Reese and Malcolm. Hal is also busy, secretly betting on and entering Jaime in baby competitions.
Hal and the boys slash the prices of their Christmas trees to outsell a nearby church. Back at the ranch, Otto's bickering relatives descend, reminding Francis of home sweet home.
Neighbors have the annual "The Wilkersons are gone" block party until they come home early. Reese and Dewey set up a plan to get money by letting Reese-tortured kids get revenge. Hal and Lois enter a kielbasa-eating contest and Malcolm unknowingly assists a robbery, but a surprising twist comes in the end.
Malcolm alerts the A.C.L.U. when he encounters censorship working on the high-school literary magazine; Hal tries to flirt with the woman in his office responsible for cutbacks.
Jamie's babysitter coerces Malcolm into doing a "small" task for her; Dewey finds a friend, only to lose him to Reese; Francis persuades Otto to confront an old adversary that once courted Gretchen.
Malcolm gets his tongue pierced and needs to hide it for a month. While Lois' mother, Ida, comes and annouces that she will marry a rich Chinese Man that she met on a cruise. Malcolm gets complications when his tongue ring gets infected, rendering him unable to say "S's" and he discovers that Ida has been drugging her fiancé with opiates and mood enhancers. When Lois and Hal confront Ida, she drugs them with free food. But luckily, the fiancé misses a drug treatment, and realizes that Ida is a terrible woman and he leaves her at the altar. Malcolm is punished for his tongue piercing. Meanwhile at the ranch, Otto decides to hire a murder mystery acting troup, but it all turns out badly.
Malcolm is convinced to play Softball by Lois and ends up doing very badly at it due to Lois's hold on him. Meanwhile, Francis tries to pick fights with Lois, Reese tries to break Francis's record of collecting toilet seats from a local junkyard, and Hal accidentally applies to become a member of the CIA.
In the milestone 100th episode, “Lois’ Sister,” Lois’ younger sister, Susan (Laurie Metcalf), pays the family a visit and brings with her expensive gifts for the boys, biting remarks for Lois and a cold shoulder for Hal – whom she has never forgiven for dumping her for Lois. Lois and Susan’s competitive relationship takes a turn for the worse when Susan gives Malcolm and Reese her prize ’65 Mustang convertible. But when Lois discovers that Susan needs a kidney transplant, she puts her anger aside and offers to donate her kidney to Susan, which Susan only sees as the perfect opportunity for Lois to one-up her.
Lois blows her top over a hidden 15 percent ser charge in the bill at her family's favorite pizza place and stages a boycott...but Hal and the boys are sneaking slices on the side. Malcom meets Angela and becomes instantly smitten with her intellectual family...but starts to feel like a heel because he's asked another girl to the school dance and is forced to break it off with her--er--them. And Francis is reluctant to let Otto hire an assistant for him...but soon comes to like the idea.
Francis is determined to show his parents why they should not have kicked Reese out. Meanwhile, Malcolm helps a football player write a college essay.
Lois tags along with Malcolm as he visits a college, but she's determined to room in the dorm Malcolm is staying in when she learns the room is co-ed. Meanwhile, after his father denies him a piano, Dewey begins stealing objects from around the house to amuse himself and to drive Hal crazy. Reese meets a girl, who he thinks is a narc, and he pretends he is a dealer, unaware that she is really an undercover cop.
Hal sets up Abe Kenarben on a blind date with Jaime's babysitter Polly but then realizes Lois has also set her up on a blind date - with Craig. Malcolm, Dewey (with his "lucky" shirt) and Reese also meet Reggie Jackson and Francis is embarrassed by Piama in front of his co-workers.
When Dewey's annual candy selling event for school comes up, he uses the excuse of "these bars help support america" to sell them. Malcolm and Stevie attempt a science experiment, and are shocked when Reese begs to help.
Malcolm convinces Dewey to do poorly on an I.Q. test, so that he won't become a ridiculed Krelboyne student. But Dewey does so badly that he is placed in a class for the emotionally disturbed. Hal and Craig compete in a dance competition.
When Lois tracks down her father's "other family," she meets Victor's "other wife" Sylvia (Betty White), and learns something shocking about her dad.
The house goes crazy as Hal is falsely charged in a crime involving his company which he has nothing to do with. He is put in an ankle collar and is immobile, forcing the rest of the family, including Piama and Francis, to pick up the slack. Everyone except Reese, who is missing after he discovers Malcolm with his girlfriend Beth. The family doesn't know, but Reese has joined the Army, where he doesn't exactly understand how the military works. Dewey also has his own problems with the family as no one listens or even knows about him leaving for a music competition.
Reese continues to be a great soldier in the Army until he finds himself in a situation where his Sergeant cannot help. But after comparing being captured to being grounded, he takes action and leads his team to victory. But being such a successful soldier has it's bad parts as well, as Reese prepares to jump from the plane - right into Afghanistan. Malcolm has his hands full as well as he attempts to prove Hal innocent. But being good with numbers helps as Malcolm notices all of the prosecutions given dates are on Fridays - which Hal hasn't worked on in over 15 years. And with Reese missing and Hal's case, Lois falls deeper and deeper into insanity.