Cece is a highly imaginative young girl who loses her hearing after a bout of meningitis at age four. She deals with the physical reality of her hearing aids and the large Phonic Ear she must wear to school, which initially makes her feel alienated from her peers. To cope with her feelings of isolation, she creates a superhero alter ego named El Deafo, using her active imagination to find agency and courage. Her journey centers on managing friendships, developing self-worth, and eventually embracing her differences as strengths.

Mike is the youngest boy in a new family that moves into Cece's neighborhood in Roanoke. Initially serving as the idealized subject of Cece's romantic daydreams, he proves himself to be a genuinely kind and observant peer. He is fascinated by Cece's Phonic Ear, treating it as an impressive superpower rather than a disability, which profoundly shifts how the other children view her.

Martha is a third-grader who lives across the street from Cece. She becomes Cece's "True Friend" and designated superhero sidekick because she is the first peer who completely accepts Cece without pity or awkwardness. An accident causes Martha deep anxiety, showing her sensitive and conscientious nature as she worries about accidentally harming her friend.

Laura is an assertive young girl who befriends Cece early on. While she does not seem bothered by Cece's hearing aids, she has a bossy and controlling personality that makes the friendship difficult to sustain. Her demanding behavior teaches Cece how to stand up for herself and set boundaries.

Ginny is a classmate who shares many of Cece's interests in books and games. Despite her good intentions, she constantly highlights Cece's deafness by speaking slowly, using exaggerated lip movements, and referring to her as her "deaf friend." Her inability to look past the disability causes friction and eventually ends their friendship.

Cece's mother is deeply invested in her daughter's well-being and success. She is proactive about finding resources for Cece, such as signing her up for a sign language class at their local church. Though she sometimes pushes Cece out of her comfort zone, causing occasional resentment, her actions are rooted in a desire to equip Cece with the tools she needs to adapt.

Cece's father is a quiet but present figure in her childhood. He occasionally travels for work conferences, bringing back small, unique gifts like a curly pencil that give Cece moments of social confidence among her peers.

Emma is Cece's best friend from early childhood, before she loses her hearing. While they share a bond from their early years, Emma struggles to understand the new challenges Cece faces with her hearing aids, unintentionally highlighting the growing gap between their experiences.

Dorn is Cece's first teacher after she receives her hearing aids. Reminiscent of Snow White, she creates a warm and supportive environment where she teaches the children crucial skills like reading, math, and the complex rules of lip-reading.

Mr. Potts is a physical education teacher who heavily favors athletic children. He lacks awareness about how to accommodate students with disabilities and inadvertently breaks Cece's Phonic Ear microphone, causing her significant distress and isolation.

Mrs. Sinklemann is a well-meaning fifth-grade teacher. While she can sometimes be strict, such as accusing Cece of cheating when she simply cannot see the board, she is generally supportive and provides creative assignments. She unknowingly becomes the subject of Cece and Mike's surveillance when she leaves the classroom.

Ashley is one of Cece's older siblings. During Cece's recovery from meningitis, Ashley acts uncommonly kind, preparing scavenger hunts and watching over her younger sister with patience.

Sarah is Cece's other older sibling. She helps keep Cece entertained during her recovery and, later, patiently explains television plots when Cece struggles to hear the dialogue.

Johnnie is a neighborhood boy who casually bullies Cece by breaking a special curly pencil she receives from her father. His actions cause Cece deep embarrassment until another peer forces him to make amends.