Michael Seater as Derek Venturi, the oldest child and the titular "Derek" of the series. Unlike Casey, he is lax-mannered and somewhat underhanded about achieving his goals and excelling in his academics, though is not entirely unkind. It is shown that he has a bond with Marti because he calls her "Smarti" and she calls him "Smerek". However, he enjoys competing with and irritating Casey. He loves to play pranks and has his own band called D-Rock in which he plays guitar. He got into Queen's University, along with Casey.
Ashley Leggat as Casey McDonald, the oldest daughter. She is idealistic and independent, as well as academically ambitious. She has a Type A personality, being very particular about her academics and frequently studies in advance and does not accept poor grades. She frequently clashes with Derek because of their conflicting personalities and because of their roles as the oldest children in the household. She loves to dance to jazz, hip-hop, and other types of music. She is also a cheerleader at some point in the show. She eventually obtains straight A's for her examinations, and got into Queen's University. In Vacation With Derek, it is revealed that Casey will double-major in English and Economics.
Daniel Magder as Edwin Venturi, Derek's younger brother. He looks up to Derek and is Derek's frequent accomplice in various schemes. He sometimes likes to stand up to Derek but then eventually backs down feeling weak
.Jordan Todosey as Lizzie McDonald, Casey's younger sister and her "sidekick". She usually sides with Casey, though as a middle child, finds common ground with Edwin. She is very patient and gives in to things her sister says very easily. She also likes to do sports such as soccer and Taekwondo.
Ariel Waller as Marti Venturi, the youngest of the Venturi children. As the youngest child, she enjoys attention from everyone in the family and can be swayed both ways in McDonald-Venturi conflicts, but can easily and stubbornly refuse to agree with anyone as well.
Simon McDonald-Venturi, the newest addition to the family. He had his debut in "Vacation with Derek." He is only shown in the movie, so he does not have a role in the show as the movie was where we last saw the McDonald-Venturi family
John Ralston as George Venturi, the father of Derek, Edwin, Marti and Simon. He works as a lawyer and was previously married to a woman named Abby.
Joy Tanner as Nora McDonald-Venturi, the mother of Casey, Lizzie and Simon. She works as a window treatment specialist.
Shadia Simmons as Emily Davis, Casey's best friend and next door neighbor who had a crush on Derek. She dated Sheldon Shlepper who moved to Newfoundland. She and Derek went on a date once, but decided it wouldn't work out when Derek admits he only asked her out to bother Casey. However, they began to date again after Derek realized he did like her and asks her to the prom. She often tries to help Casey become more popular at school, helps her fit in and helps her figure out boys along the way. According to Casey, she has a "lighthearted way of dealing with Casey's many problems". She started dating Derek in the episode "Surprise", but they broke-up before "Vacation with Derek" since Derek took interest in Roxy.
Arnold Pinnock as Paul Greebie, Casey's guidance counselor. She constantly goes to him for advice when she gets stressed; however he usually asks questions so that Casey can figure out her problem on her own. She will ask him questions and then immediately answer them herself. His last appearance is in Futuritis.
Kit Weyman as Sam Richards, Derek's best friend and Casey's first crush since she moved in with the Venturis. After receiving Derek's permission, they begin dating in the episode "Male Code Blue". After breaking up numerous times, they call it quits in the episode "Middle Manic", but decide to stay friends in the episode "Battle of the Bands" when Casey becomes the lead singer of Derek's band.
Lauren Collins as Kendra Mason, popular girl, friend of Casey's and Derek's ex after the episode "Misadventures in Babysitting". She still has a major crush on Derek, and she tries to get back together with him in "Just Friends".
Robbie Amell as Max Miller, the school's quarterback and Casey's boyfriend beginning in "Misadventures in Babysitting". He dated the head cheerleader Amy before asking Casey out. They broke up in the episode "Allergy Season". Casey wanted to get back together with him in the episode "Two Kisses, One Party", but he had already moved on.
Shane Kippel as Ralph Papadapolis, one of Derek's friends and fellow band member. In season 4, Ralph harbors a crush on Casey.
William Greenblatt as Sheldon Schlepper, he dated Emily. He is currently living in Newfoundland. All of his siblings have once been class president except him.
Keir Gilchris as Jamie, Lizzie's best friend who harbors a crush on her.
Kate Todd as Sally, Derek's co-worker who starts to like him after breaking up with ex-boyfriend, Patrick. With some interference and planning from Casey and Nora, they finally begin to date. Sally and Derek break up after Sally decides to go to UBC get back together soon afterward, then break up for good when Sally actually goes to Vancouver.
Joe Dinicol as Truman French, a new boy in school that Casey has recurring dreams about. Casey denies her feelings for him, but in the end, finally agrees to date him. Truman first appeared in "6½". They agree to go with each other in "No More Games" and they start going out in "Teddy's Back." They break up in the episode "Truman's Last Chance" because Casey sees Truman being kissed by Vicki and think it's vice versa. Casey was upset, but she reunites with Truman at the prom, and they reconciled in "Surprise;" however, they broke up before "Vacation with Derek."
Alex House as Trevor, a "punk" boy who goes to Casey's school. Derek bets Casey she can't get him to ask her out, and Casey takes the bet, soon developing a crush on him. She loses the bet after telling him about it due to Derek interfering and making her feel guilty for lying to him. She finds out Trevor was only hanging out with her because he had a crush on Emily, but the two stay friends.
Adam Butcher as Noel Covington, an "artistic" boy who Casey befriends when he auditions for the lead role in a play on a dare, and, surprisingly, gets it, which leads him to co-star with Casey. He develops a crush on her. In the episode "Just Friends", Casey begins hanging out with him to prove to Derek that a guy and a girl can be friends, but it backfires when Noel thinks Casey asked him out on a date. He returns for his role in the episode "Just Friends" one last time before the end of the series.
Hannah Lochner as Michelle, who first appears at Lizzie and Edwin's birthday party and becomes Edwin's girlfriend after kissing him there. Although she only appears in three episodes, she is often mentioned.
Sarah Gadon/Paula Brancati as Victoria "Vicki", Casey's cousin from Toronto. She and Casey appear to be friendly but tense terms when Casey and Derek volunteer to organize the wedding reception of Vicki's mother and Casey later finds out that Derek and Vicki kissed when nobody else was aware.