During Grandma's unwelcome visit with the family, she loses her leg while saving Dewey from a moving truck. Consumed with guilt, Dewey is determined to find his Grandmother's leg and give it the proper burial. Francis, on the other hand, begrudgingly becomes the caretaker for his stubborn, cranky grandmother. Meanwhile, Malcolm and Reese are given a new idea for a prank that forces them to stay awake days at a time to avoid the embarrassment of having their faces glued to the floor.
Malcolm is a regular high school kid trying to navigate his way through life despite the various obstacles thrown in his way a complete misunderstanding of girls, the constant burden of masterminding plans to get himself and his brothers into or out of trouble, and a miserable job at the Lucky Aide not to mention a severe case of teen angst.
Although Malcolm has a genius IQ, he can't seem to make sense of the opposite sex, much less his embarrassing family. Lois is the outspoken, opinionated mom, who still manages to rule the roost even though her boys are growing wise to her crafty ways. Hal, a dad who is just a bumbling, big kid at heart, often finds himself creating more chaos than his five boys combined.