Unlike previous incarnations, Sabrina Spellman in this series is depicted as a 12-year-old attending middle school. As in the original comic series, Sabrina lives with her two aunts, Hilda and Zelda Spellman, and her loud-mouthed cat Salem Saberhagen, all of whom advise Sabrina on the use of magic. It is considered a spin-off of the live-action series and borrows certain elements from it, but is obviously set in an alternate universe, as it contradicts the live-action show's premise of Sabrina not knowing about magic prior to her sixteenth birthday.
Most episodes center on the typical problems of middle school, along with those that stemmed from Sabrina's inexperience with or misuse of various magic, witchcraft, and extremely powerful and complex spells. Sabrina and her best friend Chloe would often use magic (often from the "Spooky Jar"; a cookie jar containing a genie-like being in the family's kitchen) for all sorts of perceived emergencies, ranging from trying to fit into skinny new clothes to turning Sabrina's crush Harvey into a superhero. By the end of each episode, her innate magical abilities would unintentionally backfire and Sabrina would learn that using magic usually is not the solution to her day-to-day problems.
- Sabrina Spellman: Sabrina is a half witch–half mortal that won't become magically empowered until she's sixteen, but she is able to borrow spells from her aunts Hilda and Zelda using a magical "Spooky Jar", which she often does. However, she usually finds that her meddling turns situations from bad to worse. Her friend Chloe is aware of Sabrina's magic but Harvey Kinkle, another friend and her romantic interest, isn't. She is secretly in love with Harvey and wants one day to marry him. She wears a white tank top with a pink stripe, a green moon-shaped earring paired with a yellow star-shaped earring, pink skirt, pink hair-clips in her bangs, with white and pink sneakers. When she casts a spell the magic produced is pink and yellow.
- Hilda Spellman and Zelda Spellman: While Hilda suggests they bend the rules a little and use magic to get ahead, Zelda is determined to say no right up until the moment she gives up. Hilda is more carefree and reckless than her cautious sister Zelda, and, although they do butt heads sometimes, they are still sisters. In this series and Sabrina's Secret Life, Hilda and Zelda both have the appearance of teenagers, as this was the punishment they received from Enchantra for "abusing magic" in the past. In the animated series, Zelda wears a red blouse and blue bell bottom pants in addition to a pair of blue glasses, and has long red hair. Whenever she casts a spell, the magic produced is always blue and yellow. Hilda wears a purple minidress and has olive skin, with brown hair that is shorter than Zelda's. When she casts a spell the magic produced is purple and yellow.
- Salem: Salem knows the right buttons to push to talk Sabrina into just about anything, and he does it guiltlessly—until he's caught. Salem was once a powerful wizard, but he was locked into a cat-form because he was constantly trying to take over the world. However, he makes up for his predicament with magical trinkets that help Sabrina in some situations.
- Uncle Quigley Spellman: Uncle Quigley is an original character created for the animated series. He is Sabrina's maternal great-uncle, and the household's adult guardian. Because Uncle Quigley doesn't have any magic powers, one understands that Sabrina's mother is a mortal.
- Chloe Flan: Chloe is Sabrina's best friend. She's the only mortal besides Uncle Quigley who knows Sabrina's secret.
- Harvey Kinkle: Harvey has a cute and sweet personality. While he only admits to Sabrina that she is his "best pal," he likes her very much. However, Harvey is unaware Sabrina is a witch although often sees the results of the magic himself.
- Gem Stone: Gemini is snobby, pampered and very prissy. Gem lives down the street and sees Sabrina as her main competition for Harvey's attention (whom Gem is interested in as well), though Harvey likes Sabrina more.
- Spookie Jar: Spookie Jar is a genie (or possibly a demon of some kind) who resides in a purple cookie jar in Sabrina's kitchen. Whenever Sabrina needs a special spell, she can get one from the Spookie Jar, but they rarely turn out the way she expects. Spookie Jar speaks entirely in rhymes.
- Pi: Pi is Harvey's best friend. He is very smart and quite unusual in his own special way. His eyes are never seen because his pork pie hat obscures them. He has been described by Sabrina as "totally out of it and really smart at the same time."
- Slugloafe: Slugloafe is the fat bully who calls Harvey Kinkle by his last name. His real name is Horace. There have been times where he compliments Harvey.
- Bernard: Bernard is a small, bald, nerdy boy with glasses. He is often bullied by Slugloafe and easily bossed around by Gem.