Malcolm, played by Frankie Muniz, is the show's main character and the middle child of the family. In the episode "Stock Car Races", Hal reveals that Malcolm is named after a race car driver called Rusty Malcolm (he mutters that it took two children to win that argument). At the beginning of the series, Malcolm's 5th grade teacher recognizes him as a gifted student and places him in an accelerated learning class. Much to his dismay, the move brands him as a "Krelboyne", a reference to Seymour Krelboyne from The Little Shop of Horrors. His trademark is that he breaks the fourth wall in almost every episode. (or every episode)

Many episodes revolve around Malcolm's attempts to reconcile his genius-level 165 I.Q. (it is revealed in an episode that while Lois was pregnant with Malcolm, Hal was trying to teach Reese, but in the failed attempt to teach Reese, the yet to be born Malcolm got every bit of it) with his desire to lead what he would consider a normal social life. However, Malcolm remains a social outcast in school. In middle school, Malcolm uncomfortably socializes with his fellow Krelboynes, but when the group moves on to high school, they no longer have classes together and stop interacting. Malcolm and Reese, particularly toward the end of the series, have no discernible group of friends. At this point, the only people Malcolm interacts with socially on a regular basis are his family, his genius best friend Stevie Kenarban, and a handful of short-term girlfriends.

Despite having an almost genius level IQ, he is shown to panic in extreme situations. An example would be when a girl who was at Malcolm's house brought a gun, Malcolm paniced and tried to hide, eventually trying to destroy it with a hacksaw, unintentionally causing the gun to fire.

Malcolm has had five jobs in the series. His first was as a babysitter for a rich family to earn money to buy a robotics kit, but he quit after learning that family's parents were spying on him. Later, in the middle of the series, Lois forced Malcolm to take a job with her at the Lucky Aide to have him under her control. He hated the job and had tried to quit many times but Lois would not let him. He finally quit at approximately the time he graduated. In the final episode he gets a job as a janitor at Harvard to help with his tuition. At some point, he was also granted a tutor job for a blonde girl he later did. He also had a job betting on horses which he shared with Reese.

In the final episode it is revealed that Malcolm's parents do not plan for him to be happy in life. Because Malcolm consistently exceeds his parents' expectations, by the time he graduates high school, they have the highest of expectations for him: that he will become President of the United States. Pursuant to this, instead of letting Malcolm take a six-figure job out of high school, his parents force him to follow through on plans to attend Harvard as part of an elaborate plan for his future. Lois says that at Harvard, Malcolm will have to work harder than his classmates and will accomplish more than they do, but they will continue to look down on him. Consequently, Malcolm will realize that there is more to life than showing off how smart he is. After college, the plan provides for him to channel his energies into a political career, and after starting off as a district attorney or running a foundation, he will be elected governor of a mid-size state and then President. Lois and Hal envision that he would then become one of the greatest Presidents ever because he would represent the interests of people like his family, which, his parents say, no other President has. It appears that his brothers and grandmother are aware of these plans, as when Malcolm looks around at his family after being told this, they all nod at him, and Francis says, "Sorry, we thought you knew." Although Malcolm recognizes that his parents' plans are outlandish and improbable and complains that they are making decisions for him that are rightfully his to make, he signals that he has accepted their vision for him and will carry it in his valedictorian speech at his high-school graduation. Even though he is the younger Brother of Reese, in real-life, Frankie Muniz (Malcolm) is more than two months older than Justin Berfield (Reese). (Berfield was born February 25, 1986 and Muniz was born December 5, 1985)

Malcolm's egotistical and antisocial personality is believed to have been inspired by the character of Holden Caulfield, protagonist of the novel The Catcher in the Rye. Malcolm is often heard calling others "phonies," a habit shared by Holden.