List of Characters of the series.
- Jesse McCoy (Spencer Klein, Shawn Pyfrom, Justin Bradley) - Jesse The main character of the series, he is not the smartest kid in the school, and he is often picked on by friends including Vinnie because his mother treats him like a baby and embarrasses him. Whenever he has a task or homework to do, he usually gets out of it by telling a lie to Miss Graves or sometimes his mother, but both of them catch on and give him different punishments. Jesse is bald and wears an orange sweater with blue jeans.
- Nancy Francis (Mindy Cohn) - Nancy is a red-haired girl with horn-rimmed glasses. Nancy is always trying to fit in and helps Jesse out a lot because he is picked on. Albeit good-natured, she is sometimes bossy. She is always trying to befriend Penny, but she is unsuccessful at that, and will sometimes end up being "friends" with Polly McShane who she resists instead.
- Penny Grant (Tara Strong) - Penny is one of the wealthiest girls in the entire school, as well as a very charitable and kind person. Penny is not a snob despite the common stereotype following rich kids in modern day cartoons. She has blonde hair that helps her fit in very nicely. Nancy and the other girls from the class try to befriend her because of how wealthy and kind she is, but sometimes Penny doesn't even realize that she is rich, and that Nancy and the other girls are always trying to befriend her (although she doesn't despise them).
- Vincent 'Vinnie' Nasta (Pamela Adlon) - Vinnie is the prankster of the class. He is a tall boy who likes to pull pranks on people. Vinnie wears a football shirt and has spiked up black hair. He is also friends with Jesse, and the two pull pranks together on occasion, although sometimes he picks on Jesse mainly due to how his mother treats him. Vinnie has a big brother named Tony, whose former school projects Vinnie often tries to pass as his own but Miss Graves always remembers having already evaluated them during Tony's time. Vinnie once lost his friends when they learned his aunt married Mr. Besser but fortunately the wedding was short-lived.
- Freddie Fay (Bryton McClure) - Freddie is basically classified as a nerd in the school and he often bemoans that fact. He has glasses, black hair, wears a yellow shirt and sticks out as an easily found school nerd. In one episode everyone picked on him because they thought he had wet his pants, when actually the water fountain sprayed him by accident.
- Polly McShane (Colleen O'Shaughnessey) - Polly, a proud Lithuanian, is considered a "teacher's pet" in both demeanor and appearance. Polly is very smart and has glasses, brown hair and a plaid dress. The other children can usually detect her presence due to her constant yodeling and obnoxious disposition, especially because of her loud voice. She has an obsession with spoons. She is also well known for wanting to be the life of the party and be on top of everything, and for being a gossip and tattle tale to the heads of the school over other children she catches behaving badly. She has a pet goat named Schnitzy.
- Arthur Kenneth Van der Wall (Christoper Marquette) - An upper-class boy who is usually attempting to sell abnormally extravagant goods to the other children in the class. He has brown hair and wears a blue suit.
- Jordan (Lauren Tom) - A girl who is very rich, but keeps that in a secret. Nancy finds out in one episode, promising Jordan to keep the secret out of fear her friends will think she's a snob. To keep them from knowing, she never invites anyone to her house, which ironically caused some people to think she's poor. However, when Nancy bragged so much about having a wealthy friend (without telling anyone she was referring to Jordan) her other friends started avoiding her like Jordan feared would happen to her if they knew she was wealthy.
- Gabrielle (Olivia Hack) - A girl who is usually seen with Jordan and Nancy. She mostly goes along with everything Jordan thinks or does, and although she is Nancy's friend, sometimes argues with her.
- Mary-Ellen (Colleen O'Shaughnessey) - A girl who is one of Nancy's friends. Doesn't have much participation in the series.
- Piggy (Justin Jon Ross) - A slightly fat boy with glasses who is also a minor character, and doesn't interact much with the others.
- Tillie (Tifanie Christun) - Another of Nancy's friends, a tall redhead who is somewhat self-absorbed.
- Jenny (Jane Woods) - A girl with red glasses who doesn't have much participation in the class.
- Sanjay (Tara Strong) - An Indian student with dark hair, a dark red shirt, and speaks with an accent. He is often annoyed by Polly.
- Charlie (Terrence Scammell, Crystal Scales) - A boy who looks slightly similar to Sanjay, with dark hair and a red shirt. He often wins what Nancy should have won. In one episode, the class switched seats to fool Mr. Besser when he became a substitute teacher, and when Nancy's report was worth an A, Mr. Besser mistook her for Charlie due to the seating arrangement plans (since he knew few of the students' names except Jesse and Vinnie, whom he often put in detention). And when Jesse got glasses that he couldn't see with, he was the swing vote between Nancy and Charlie, and, while intending to vote for Nancy, voted for Charlie by mistake because he couldn't see the names clearly.
- Melanie Bellanchof (Janyse Jaud, Debi Derryberry) - A newer student to the school, she is Mrs. Bellancough's daughter and a recurring antagonist, her parents are either divorced or split up, as Melanie comes to town to live with her mother. She doesn't like living with her, and when referring to anything that she doesn't like will say either "Don't know", "Don't care" or "Smells". At her house, she is mostly seen on the phone talking to a friend from her old school named Gloria.
- Zack (Sam Saletta) - The Bully of the school and the other antagonist.
- Miss Gracie Graves (April Winchell) - Miss Gracie Graves is a really great teacher. She acts as the voice of reason, which is why most of her students go to her whenever they seek help or advice.
- Mr. Stuart Besser (Rodger Bumpass) - Mr. Stuart Besser is the incompetent principal of the school and the main anatgonist. Noted for his stupidity and overweight stature, he is often satirized, whether it be vocal or written, by his students. His negligence and ignorance serves as recurring comic relief within the television show. Mr. Besser was once married to Vinnie's aunt, much to the shock of both males (Vinnie didn't know Mr. Besser was his aunt's husband and Mr. Besser didn't know Vinnie is his wife's nephew until the two of them met during the wedding party), but the wedding ended when she learned he expected to live at her expenses. Mr. Besser was oblivious to the fact Vinnie didn't like being his nephew.
- Nurse Pitts (Lori Alan) - The school nurse. She's obsessed with illness and also talks a lot about death.
- Coach (Bruce Dinsmore) - The school gym teacher.
- Roberta McCoy (Edie McClurg) - Jesse's overprotective mother. She usually treats Jesse like a baby and embarrasses him in front of his friends who sometimes mock him.
- Amy Bellanchof (Pauline Little) - Melanie's mother who is a teacher attending Melanie's new school. However, as she didn't have a lesson plan, her students made little progress, which put her on the verge of getting fired. Although Miss Graves helped her improve her class by sharing her lesson plan, Mrs. Bellanchof dishonestly passed Miss Graves' plan as her own to win an award. In other acts that show her lack of honesty, she got custody of her daughter by lying to the judge about which parent Melanie would rather live with, and used her position at the school to have her daughter join the cheerleading squad despite Melanie trying to tell her she doesn't want to be a cheerleader. She also loses her temper easily, especially when Melanie complains and tells her she wants to go back to live with her father, pulling her hair and screaming when she is overly angry or stressed.
- Mrs. Francis (April Winchell) - Nancy's mother.
- Mrs. Myerson (April Winchell) - She is an obese woman with a very pleasant and respectable disposition. She wears a pink dress and has yellow hair. She lives in a neighborhood around the school. She briefly appears a couple of times in the episode "Bing, Bing, Bing, and a Shot."
- Mr. Miller (Mel Brooks) - He is the pool official of a pool in Miami that Nancy goes to visit. He gives her a hard time about things like hygiene. He appears in the episode "Squeezed Out."