Dennis Mitchell - a precocious but lovable, freckle-faced five-and-a-half-year-old boy with a famous blond cowlick and a penchant for mischief. His long-suffering parents can only shake their heads and try to explain their son's antics to others. Despite this, they really do love him very much. Dennis' wide-eyed curiosity, his well-meaning attempts to help, his innocent, matter-of-fact bluntness and his youthful energy and enthusiastic nature always seem to lead to trouble wherever he goes (most often at Mr. Wilson's expense). He wears a blue/black striped shirt, tennis shoes, and red overalls with pockets that are sometimes filled with snakes, frogs, or his slingshot. He hates carrots and baths, loves root beer, ketchup, mud puddles and TV Westerns (especially those starring Cowboy Bob), and has occasionally been depicted wearing a cowboycostume.
Henry Mitchell - Dennis' father is a workaday aerospaceengineer. Henry seems to understand Dennis more than his wife does especially in affairs of the heart. One example was when a furious Dennis stormed in saying, "Wimmin can say some of the stupidest things!"; Henry knowingly said to Alice, "Margaret." Also, while he was watching Gina, he confides to his dad, "There's somethin' about Gina that I can't figger out." Henry, wisely, advised his son, "Wait." Another time, he and Alice overhear Dennis tell Gina that she "smelled better than a plateful of Peanut Butter samwiches"; Henry replies, "The ultimate compliment". Like his creator Hank Ketcham, Henry served in the US Navy. Sometimes, he and Alice will get into arguments (which even showed his chauvinistic side at times), but they remain devoted to each other.
Alice Mitchell, née Johnson - Dennis' stay-at-home mother Alice is usually the reassuring figure Dennis can run to when things get too overwhelming, ready to greet him with a warm hug. As a running gag, Alice Mitchell has a phobia of snakes. Another running gag involves Dennis' ever-changing parade of new babysitters. No one will take the job twice. Alice is also known for punishing Dennis' misbehavior by having him sit in the corner in a rocking chair for timeout, although a couple of times she has instituted tougher discipinary measures such as spanking, where Dennis is shown crying or grumbling about the adversity.
Ruff - Dennis' big, lovable, faithful dog (an Airedale mix) and best pal. Ruff is always eagerly following him around, accompanying him while Dennis is running, riding his bike or his skateboard.
Hot Dog - Dennis' rarely seen cat, who usually commiserates with him while he sits in the corner and reflects on his wrongdoings.
Grampa Johnson (Oliver "Swede" Johnson) - Alice's father who spoils Dennis often. He evokes the unintentional jealousy of Mr. Wilson, for he gets to see Dennis only on occasion, but Mr. Wilson sees him all the time. Because they are so much alike, Dennis and Grampa Johnson get along beautifully. Mr. Wilson also thinks that Johnson should act his age, but this advice is often ignored. To Grampa, life is worth living and he encourages Dennis to live it to the fullest.
George Everett Wilson Sr. - Dennis's cranky, cantankerous middle aged next-door neighbor; a retired postal carrier and (at least as far as Dennis is concerned) his best human friend. Dennis likes Mr. Wilson but unintentionally annoys him, as he regularly disrupts Mr. Wilson's attempts at a serene, quiet life. Dennis often interrupts Mr. Wilson's hobbies such as gardening, as well as coin and stamp collecting, at times accidentally damaging his property. As a result, the gruff old retiree displays a less-than-cordial attitude towards the young boy, though Dennis continues his well-meaning intrusions unabated. Actually, as many readers suspected, he is secretly fond of Dennis and misses him when he's away - although he'd never openly admit it. Mr. Wilson is named after a teacher Hank Ketcham knew. Dennis will often (especially in the TV series) refer to him as "Good Ol' Mr. Wilson".
Martha Wilson - Mr. Wilson's engaging wife, who adores Dennis. Mrs. Wilson freely dotes on him and plies him with freshly baked cookies and milk. Martha sees Dennis as a surrogate grandson.
Earl Wilson - Mr. Wilson's Estranged Son.
George Wilson Jr. - Mr. Wilson's Son.
Tammy Wilson - Mr. Wilson's Daughter.
Edna Wilson - George Jr.'s Wife.
George Wilson III - Mr. Wilson's Grandson.
Will Wilson - Mr. Wilson's Grandson.
Helga Wilson - Mr. Wilson's Granddaughter.
Tommy Anderson - Dennis's best friend (after Mr. Wilson). This character eventually disappeared from the strip.
Joey McDonald - loyal, timid and not too bright (but he's a year younger), he usually plays the sidekick to Dennis's schemes, and sees him as a big brother figure. Dennis often gives him advice, and gives him little "nuggets" of wisdom and insight.
Margaret Wade - a freckled, red-haired, bespectacled know-it-all whose cloying and self-important demeanor is always getting on Dennis’s nerves. She is attracted to Dennis and is stubbornly confident in the belief that she will marry him when they are adults, but he will have none of it because Dennis clearly has no interest in her. She always tries to improve Dennis and his manners, but only succeeds in annoying him. She has a certain amount of dislike for Gina, whom she sees as her competition. Gina gains Dennis's respect and admiration by just being herself and Margaret's pretensions fail to make a mark on him.
Gina Gillotti - a fiercely independent young Italian American girl, who Dennis is mostly unaware he secretly has a crush on. Gina is tomboyish yet still feminine in appearance. She also likes Dennis in a future romantic way, but unlike Margaret, Dennis actually enjoys being with Gina. He likes her because she is as independent minded as he is, and she enjoys the same things that he does. Gina is also highly aware that she is a girl, and woe betide anyone who doesn't think so. It is presumed that Gina is the oldest of the kids.
Jackson - in the late 1960s, Ketcham decided to add an African American character to the cast named Jackson. Ketcham designed Jackson in the tradition of a stereotypical cartoon pickaninny, with huge lips, big white eyes, and just a suggestion of an Afro hair style. In one cartoon that featured Jackson, he and Dennis were playing in the backyard, when Dennis said to his father, "I'm havin' some race trouble with Jackson. He runs faster than me." The attempt to integrate the feature did not go over well. Protests erupted in Detroit, Little Rock, Miami, and St. Louis, and debris was thrown at the offices of the Post Dispatch. Taken aback, Ketcham issued a statement explaining that his intentions were innocent, and Jackson went back into the ink bottle. However, another African American character named Jay Weldon appeared in the 1986 animated series to far less controversy as he was not a stereotype.
Cowboy Bob - A film cowboy whom Dennis idolizes. Appears in a series of westerns known as Cowboy Bob films. Dennis fails to realize that westerns are rarely made today and that the films he is seeing are actually re-released from long ago. In one story arc where Dennis' parents invite the retired actor to a party, they have Dennis meet him, to which Dennis comments he must be "Cowboy Bob's grandpa!"