Humphrey is a golden hamster and the class pet of Room 26. Thanks to a tiny notebook and pencil from his original owner, he learns to read and write English, though humans only hear his vocalizations as squeaks. He considers himself a student of the class and keenly observes human behavior. His cage features a broken lock, allowing him to leave at night to explore the classroom and intervene in the students' personal problems.

Mrs. Brisbane is the regular teacher for Room 26 at Longfellow School. She is short, has gray hair, speaks in a soft voice, and tends to wear dark clothing. She expresses immediate dislike for the class hamster left by her substitute. Her stern demeanor in the classroom masks the heavy stress she carries from caring for her injured husband at home.

Ms. Morgan McNamara is a young, lively substitute teacher who fills in for Mrs. Brisbane at the beginning of the school year. She believes taking care of an animal teaches students about themselves and buys Humphrey to fulfill this educational philosophy. She leaves Longfellow School to accept a teaching position in Brazil.

Sayeh is a gentle, intelligent student in Room 26 who aces all her written tests but rarely speaks aloud. Humphrey nicknames her "Speak-Up-Sayeh" because of Mrs. Brisbane's constant requests for her to participate. She hides a beautiful singing voice and stays quiet because English is her second language, fearing her peers will mock her accent.

Mr. Morales is the principal of Longfellow School, viewed by Humphrey as the most important man in the building. He always wanted a hamster as a child but was never allowed to have one due to family finances. While students respect his authority at school, he struggles to maintain any discipline over his own children at home.

Aldo is the cheerful, mustache-wearing night custodian at Longfellow School. He cleans the classrooms while dancing and singing along to the radio. Despite his lively exterior, he feels isolated working the graveyard shift and relies on the class hamster for silent company during his dinner breaks.

Garth is a student in Room 26 who suddenly shifts from a normal classmate into a bully, shooting rubber bands at other children. He directs significant aggression toward Humphrey, calling him a rat and attempting to scare him. His sudden shift in behavior masks deeper family stress that he keeps hidden from his peers.

Bert is Mrs. Brisbane's husband. An automobile accident has left him using a wheelchair, causing him to become bitter and angry at his restricted mobility. He initially resents Humphrey's presence in his house, viewing the caged animal as a reflection of his own physical limitations.

A.J. is a boisterous student whom Humphrey nicknames "Lower-Your-Voice-A.J." due to his high volume. He lives in a household where the television and radio blare constantly, forcing everyone to shout to be heard. He is Garth's former friend and the frequent target of his rubber bands.

Miranda is a kind student with golden blonde hair, earning her the nickname "Golden-Miranda" from Humphrey. She lives in an apartment with her mother and a large, poorly-behaved dog. She is diligent about her duties as the class pet monitor.

Richie is a student in Room 26 who frequently needs instructions repeated. He comes from a large, loud extended family and takes a turn bringing Humphrey home for the weekend.

Mr. Nasiri is Sayeh's father. He speaks only a little English and feels hesitant about practicing, contributing to the family's overall language barrier at home.

Mrs. Nasiri is Sayeh's mother. She does not speak English and feels self-conscious about learning it until Humphrey's presence gives her a non-threatening subject to talk about.

Maria is a woman who attends the Moonlighters Club. She meets Aldo there and begins dating him, eventually meeting his extended family during a weekend gathering.

Brenda is the seven-year-old daughter of the school principal. She is energetic, lacks boundaries with animals, and frequently ignores her father's instructions.

Willie is the five-year-old son of the school principal. Like his sister, he is hyperactive and dismissive of his father's attempts to maintain discipline in the house.

Mrs. Morales is the wife of the school principal. She works in real estate and leaves the childcare to her husband during her showings, forcing him to manage their energetic kids on his own.

Mr. Thomas is A.J.'s father. He maintains a loud household where the television is always running, though he remembers a childhood spent playing card games without screens.

Mrs. Thomas is A.J.'s mother. She keeps the volume in the house high to hear broadcasts over the daily commotion of raising her children.

Mr. Tugwell is Garth's father. He manages a highly stressful home environment and coordinates with the school to help address his son's sudden aggressive behavior.

Miranda's mother lives in an apartment with her daughter and their dog. She runs errands on the weekends and attempts to keep the pet dog secured.

Jason is the adult son of Mr. and Mrs. Brisbane. He lives far away in Tokyo, Japan, leaving his parents alone in their quiet house following his father's accident.

Clem is Miranda's large, intrusive dog. He is skilled at nudging doors open and poses a direct physical threat to the small class hamster during weekend visits.

Heidi is a student in Room 26 who frequently speaks out of turn. Humphrey nicknames her "Raise-Your-Hand-Heidi" because of the teacher's constant reminders.

Art is a student in Room 26 known for his wandering focus. He becomes a target of Garth's aggressive behavior on the playground.

Gail is a cheerful student in Room 26 who laughs frequently. Humphrey gives her the nickname "Stop-Giggling-Gail" based on classroom corrections.