Dewey, played by Erik Per Sullivan, is portrayed as being quieter and more inclined to the arts than his brothers, at least until Jamie was born. It was noted in one episode that Dewey was exposed to radiation from a cracked microwave while in the womb. He hides his intellect from Malcolm and Reese, in many cases cleverly taking advantage of them. But for much of the series he is frequently beat up and picked on by Reese and Malcolm. In one episode he fools Reese into believing he is forwarding instructions from their mother when in fact he is making them up while talking to a telemarketer, Francis, a time and temperature lady, or even no one on the phone ("Hal's Friend"). Despite being a genius like his older brother Malcolm, Dewey is the opposite in terms of personality. There is a chance that Dewey downplays his intelligence where the rest of his family are concerned, perhaps so that Hal and Lois would not try to invest time in influencing his personal life, much like they do with Malcolm.

Dewey is sometimes abnormally calm and stoic in dangerous situations, as in "Zoo" when he and Malcolm are trapped in a tiger pit and the show almost ends. Dewey assures his brother that "everything's going to be alright" while they are staring into the mouth of a tiger.

Dewey longs for attention, especially in Future Malcolm, where he tries to convince his parents that the baby is talking to him from within the womb and forcing Dewey to do crazy things such as painting a wall green, driving the family car and breaking a stack of crockery (however, Dewey simply wanted attention and an excuse to cause havoc). As the series progressed, most episodes involving Dewey would have him viewed as a manipulator when dealing with his brothers or parents. Examples of this are the episode Stevie in the Hospital, when he made Lois think she was losing her mind by messing with her clothes and daily routine, and in Dewey's Opera, when he fueled a fight between Lois and Hal so he would have better material for the opera he was writing based on their fight. In Baby Part One, Dewey was angered to learn that his parents, or possibly just Hal, had completely forgotten that the day they planned to induce labor on Jamie was his birthday. He got back at Hal when, at the Bridal Expo they were attending, Dewey went around collecting sympathy from people who were working at the expo by telling them his story. They then set it up so Dewey could reveal what Hal did to the entire convention in order to publicly shame him.

In the fourth season, Dewey begins to exhibit a high degree of intelligence, seen mainly in his talent of playing the piano; in one episode (Malcolm Visits College), Dewey even manages to make a fully functioning organ out of various appliances and objects, simultaneously driving Hal insane with the disappearing objects (Hal had previously refused to buy Dewey a piano to play). Dewey is about to follow his brother into the gifted class, only to have Malcolm help him stay in normal classes. Malcolm has Reese complete Dewey's test, which accidentally gets Dewey thrown into the "Special" class, which is full of kids considered lost causes. Students in this class are known as the "Buseys" (a reference to actor Gary Busey). Dewey has since organized the class to desire more normalized expectations, and taught them standard lessons. He has been trying to show that they are just as capable as others, and has organized them to do things such as performing an opera he wrote based on his family. Unlike Malcolm, his parents intend for Dewey to be rich and happy later in life. Lois even once told Malcolm that "Dewey is a flier, he'll just drift and float through life and things will turn out for him, but you and I, Malcolm, are burrowers, we are at our best when our heads are down and we're grinding through a mountain of drudgery."

By the Seventh Season, it seems that Dewey is no longer in the "Buseys" class; however, it is not specified whether Dewey had been restored to mainstream classes, or if he had been transferred to the Krelboynes.

Dewey spends much effort making sure his brother Jamie does not feel neglected as he did. Jamie once showed Dewey a pearl necklace, as a result Jamie and Dewey went on a treasure hunt looking for the "stash" (where Francis' hid Lois' jewelry) as part of a back story, in the end it turned out that Jamie was stealing jewelry from their neighbor's house. In Morp, Dewey learns that his parents have practically no baby photos, or photos of him growing up. He then stages an elaborate scavenger hunt for his parents to complete, after Lois and Hal kicked him out of the house to have sex while Malcolm and Reese were at their prom and Hal gave him his wallet. Dewey had the two collecting party supplies and food, and then spent the rest of Hal's money renting out a video arcade. Lois and Hal learned he did it so Jamie could have his own private party, and to give them an opportunity to not ignore him growing up like they did him. While Lois still punished him, she admitted it was a nice thing he did for his brother.