"Krelboyne", the name of the class of gifted students to which Malcolm belongs, is taken from the name of the nerdy hero of The Little Shop of Horrors.
Scenes from One Million Years B.C. can be seen during the opening credits. In one of them Raquel Welch is shown in the claws of a monster bird. The other scene shows the fight against a giant turtle.
On the show, Reese is the second oldest brother of Malcolm, but in real life Reese (Justin Berfield) is less than three months younger than Malcolm (Frankie Muniz).
The hamster that Dewey releases in an earlier episode can be seen in various episodes after, rolling past the screen (in its exercise ball) on the ground in the background.
In the episode where Hal and the boys go to the race track, they come home to discover that Lois had gone through all of their stuff, in that pile was a pack of Morley cigarettes, the same fake brand the Cigarette Smoking Man prefers to use on The X-Files.
Jane Kaczmarek in real life has given birth by way of Caesarian section three times. When it came time to simulate giving birth without a C-section in the episode Baby Part Two, Jane just imitated every other birth she had seen on television.
In the opening credits, the boxer who inadvertently knocks out the referee is Pedro Cardenas, fighting Willie deWit. He accidentally KO'ed referee Bert Lowes during the 1982 North American Championships in Las Vegas.
Actor Patrick Bristow first appears in the Episode "Ida's Boyfriend" as Phillip, the head of the Acting troupe hired to hold a Murder Mystery at the Grotto. Later, Patrick Bristow returns to the show as Lloyd, Chad's Father in the episode "Chad Sleep's Over".
None of Malcolm's family have a last name. While in military school, Francis was referred to only as "Francis" and never by his last name. Reese joins the army and we learn the last name of his fake ID is "Jetson" but there is no indication that that is his real name.
Although the family's surname was revealed as Wilkerson in the pilot episode, it was decided afterwards that the family shouldn't have a last name. A running joke on set was that the family's last name was 'Nolastname'. This is officially confirmed in the final episode "Graduation" when Francis drops his work pass and his surname is briefly seen. Further confirmation can be seen when Malcolm is introduced to the stage for his speech. His last name is not heard as the microphone screeches at the crucial moment but you can read the announcer's lips clearly saying 'Malcolm Nolastname'.