- Jeffrey Lionel "Maniac" Magee is the book’s protagonist. He is an orphan and finds himself in Two Mills, where he becomes a local legend while trying to find a home. He has astonishing athletic abilities, runs everywhere he goes, can untie any knot, is allergic to pizza, and crosses the barrier between the East End and West End as if blind to racial distinction. He has done many heroic feats such as running for a long period of time, hitting many home runs in a row, and entering Finsterwald's backyard.
- Amanda Beale is the first person Jeffrey meets in Two Mills. She carries her books in a suitcase so they aren't ruined by her younger siblings, Hester and Lester. She defends Jeffrey from Mars Bar and eventually provides him with a home.
- Mars Bar Thompson is the worst kid in the East End and the book's antagonist. He dislikes Jeffrey's presence in the East End, which is exacerbated when Jeffrey beats him in a race. However, he eventually rescues Russell McNab from the trolley truss, and offers Jeffery a place for a while. As his nickname implies, he is known for eating Mars Bars. His real first name is never revealed.
- John McNab is infuriated when he cannot strike out Jeffrey with his ball. After acting as a bully, he welcomes him into his home when he brings back John's younger brothers, Piper and Russell, after their attempt to run away to Mexico. He remains convinced that the black East Enders are planning a rebellion.
- Piper and Russell McNab are John McNab's younger brothers who play hookey, steal, and constantly try to run away from home. In their house, they use toy machine guns to shoot the "rebels" from the East End. Piper also had a party at the end of the book.
- Earl Grayson is the groundskeeper at the zoo and resident of the YMCA, though he was once a minor league baseball pitcher who struck out Willie Mays. He becomes friends with Jeffrey, who listens to his stories and Jeffrey teaches him to read. They end up living together in a house, which makes him responsible. He is very kind and cares about Jeffrey.
- Mrs. Beale is the kind and caring mother of Amanda, Hester, and Lester. She is very sweet and thoughtful to Maniac as well.
- Hester and Lester are the brother and sister of Amanda Beale, and the son and daughter of Mrs. Beale. They are very hyperactive, and will mess up anything that they can get their hands on by drawing on things with crayons.
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