Main characters

• Meredith Henderson as Shirley Holmes: The great-great-niece of Sherlock Holmes, Shirley is the daughter of British diplomat Robert Holmes and virologist Dr. Joanna Holmes. She carries on her famous ancestor's legacy of solving crimes through deductive reasoning while attending the prestigious Sussex Academy. In addition to Sherlock's detective skills such as deductive reasoning and disguise, she also has his mannerisms, but she can still express her emotions. She prefers to keep a low profile so she can continue her sleuthing. She wears a variety of hats throughout the series. Henderson, as Shirley, was the only character to appear in all episodes of the show.
• John White as Francis Boris "Bo" Sawchuk: Shirley's sidekick. An ex-gang member from a Ukrainian family, Bo attends Sussex Academy on a scholarship. He first met Shirley in afterschool detention and was amazed at the girl detective's deductions about him. Shirley came to his aid after he was falsely accused of setting a work shed on campus on fire. After that case was solved, Bo became her sleuthing partner and best friend, akin to the relationship between 'Sherlock Holmes' and 'Dr. Watson'. He was supposed to be colorblind in first episode however that was never mentioned again. Bo is commonly mistaken as Shirley's boyfriend. His first appearance was in "The Case of the Burning Building." At the end of the series, he leaves for Ukraine to further his studies. White, as Bo, appears in all episodes of the series except "The Case of the Forbidden Mountain," where he is only mentioned by name.
• Sarah Ezer as Molly Hardy: Shirley's nemesis, and Moriarty counterpart; her name is a reference to Sherlock Holmes' infamous foe. A newcomer to Sussex Academy, Molly first appeared as Alicia Gianelli's running mate during the school election for student council president. Through an elaborate scheme, Molly is elected student council president. Her true scheming nature is hidden from everyone except Shirley and Bo. Although her machinations are routinely thwarted by Shirley, Molly manages to escape punishment. She is revealed to be a sociopath in "The Case of the Crooked Comic" and is a mastermind of evil genius with an IQ of 160. Molly first appeared in "The Case of the Ruby Ring." It is possible that she is in fact descended from Professor Moriarty.
• Annick Obonsawin as Alicia Gianelli: Alicia first appeared in "The Case of the Ruby Ring". Alicia is a good friend of Shirley and Bo, and she works at the Quazar Cafe, often mixing up orders of her customers. However, she also bows out easily to peer pressure and appears more simple-minded and materialistic than Shirley is.
• Brendan Fletcher as Sterling "Stink" Patterson: Class clown and prankster. His parents run the local novelty store. If Molly is Shirley's 'Moriarty', Stink could be considered her 'Sebastian Moran', though while being a trouble-maker he is far less malicious. Stink first appeared in "The Case of the Ruby Ring" and his last appearance was in "The Case Of The Crooked Comic". His departure from the series was explained as Molly being unable to get Stink back into Sussex Academy.
• Blair Slater as Bartholemew "Bart" James: Bart first appeared in "The Case of the Ruby Ring." He is highly interested in the paranormal and considers it good fortune to be abducted by aliens. He is also very concerned about his studies, as seen when Math is taken out of the curriculum in Sussex during "The Case of the Calculated Crime". He may be a little queer, but Bo and Shirley still treat him as a friend, and he is aware of Shirley's sleuthing activities and sometimes helps out.
• Chris Humphreys as Robert Holmes: Shirley's fathet, The great-nephew of Sherlock Holmes. Mr. Holmes first appeared in "The Case of the Burning Building." He is mostly worried for his daughter because he knows her tendency to get involved in cases out of curiosity, and at first he had almost given up hope on finding his wife. His last appearance in the series is in "The Case of the Vanishing Virus."
• Elizabeth Shepherd as Peggy "Gran" Holmes: Shirley's grandmother and Mr. Holmes' mother. Peggy does not appear in the series after "The Case of the Forbidden Mountain" and is mentioned to have gone on vacation in the Fiji Islands in "The Case of the Vanishing Virus."
• Marie Stillin as Ms. Cynthia Stratmann: Headmistress of Shirley's school, Sussex Academy, an upright woman who always works hard to success. She appeared since first episode, The Case Of The Burning Building, where she caught Shirley arriving late to class, therefore giving her detention where she ended up meeting Bo. She has a close friendship with Mr. Howie and is a Molly Hardy supporter, unaware of Molly's true intentions.
• Colin Fox as Mr. Arthur Howie: Shirley's history teacher at Sussex. He used to attend Sussex and boarded at the dorm, and was also a very popular student, as shown in "The Case of the Dead Debutante". However, he has kinder-phobia, the phobia of children, as revealed in "The Case of the Alien Abductions".
• Maggie Huculak as Dr. Joanna Holmes: Shirley's mother, who had disappeared for several years as a result of being in Rwanda during a civil war. She, Shirley, and Robert are reunited when Mr. Holmes is offered the chance to go to Rwanda on business. It is often said that Shirley shares her curiosity and determination to never give up.

Supporting/Recurring Characters

• R. Morgan Slade as Parker. Shirley's classmate who often hangs out with Shirley's gang. However he is barely involved in a case.
• Nathan as Watson the Dog. Shirley's dog.
• Helen Roupp as Mrs. Fish. Lazy secretary of Sussex Academy. She is the opposite to Ms. Stratmann.
• Michael Puttonen as Detective Tremain. He is always wrong about his suspicions, and Shirley is the one who solves the cases instead of him.
• Phillip Jarrett as Inspector Marquee. He is often after Bo' footsteps.
• Jay Brazeau as Frank Patterson. Stink's father.
• Arne MacPherson as Adam Quincy
• Rick Howland as Bernie Szabo in "The Case of the Bouncing Baby"
• Awaovieyi Agie Father Pierre Cayobanda.
• Thomas Milburn Jr. as Kasey Zee. Reporter.
• Jonas Chernick as Daniel Devine. An artist that blamed Stink's dog as a cat killer. He also appeared as Mikola in The Case of the Desperate Dancer.
• Dave 'Squatch' Ward as Jarrod. A motorcyclist that helped Ms. Stratmann in The Case Of The Bamboozling Blonde, he also appeared in The Case of the Liberated Beasts.
• Kett Turton as Norman Melter, he replaced Stink. Somewhat eccentric guy.
• Leslie Wolos as Heather, student in Sussex Academy, she starts dating Bo in last episode. She also appeared in other episodes as a different character.
• Jennifer Lin as Bai Sung. She hides a secret about herself and suddenly turns into Bo's love interest that makes Shirley more jealous than intrigued.
• Bill Switzer as Matt. Shirley's love interest. At first they don't get along well, because Matt mistook Shirley and Bo as a couple, then both realized that they have lot in common.

Guest Stars

• Ryan Gosling as Sean. A gang boy that has issues against Bo. He tried to kill Shirley and Bo in a fire in first episode.
• John Neville as Dr. O. Henry. A young alien hidden in a human corpse that developed a close friendship with Bart.
• Diana Leblanc as Rebecca Ratcliff. An actress that has unexplained accidents behind her. Shirley suspects that she knows her mom.
• Rebecca Gibson as Angela. Rebecca's understudy. Actress in The Case Of The Second Sight.
• George R. Robertson as Bart's Grandfather.
• Shelley Duvall as Alice Flitt. Sussex librarian. Wannabe witch.
• Janet-Laine Green as Ruth Monroe. Miss Stratmann friend since childhood that is always one step behind her.
• Jennifer Clement as Constance Quick. Pretender woman that real name is Barbie Biddel "with double D". She is often receiving death threats.
• Brennan Elliott as Jake Bain. Nice rising star that is struggling with fame.
• Lisa Ryder as Jenny Bain. Singer jealous of her brother's fame.
• Crystal Lowe as Pascal. Karate Girls leader, Episode: "The Case of the Open Hand".
• Rebecca Henderson "Beki Lantos" as Mimi, Episode: "The Case of the Open Hand".

Season 1: 1997

Season 2: 1998

Season 3

Season 4