Orphan 6 takes place after Orphan: The Return of Esther Coleman,
Esther returns and kills Elise's boyfriend, so now Lucy, Hermione and Hallie must stop her before it's too late. Jerry might developed feelings for Lucy.
- Ellen Wroe as Lucy Coleman/The Main Protagonist and Esther's former foster sister.
- AnnaSophia Robb as Hermione McDonnell/Esther's half sister.
- Bobby Campo as Jerry Alton/Former Principal of Trinter High School and Lucy's love interest.
- Keke Palmer as Hallie Jones/Hermione's best friend and Esther's former foster sister
- Isabelle Furham as Esther Stein-Nightingale-Sissy-Jones-Coleman, a.k.a Leena Klammer-McDonnell/The killer
- Odette Annable as Elise Jeans/Esther's former target
- Amber Heard as Bea Sissy/Hermione's goth friend and Esther's former foster sister
- Emma Stone as Roxanne Nightingale/Esther's former foster sister
- Hayden Panettiere as Penny Looken/Elise's friend (Replaced Nikki Reed)
- Atticus Mitchell as Carlos Finkle/Elise's friend
- Emma Watson as Lizzy Lover/Bea's best friend
- Nico Tortorella as Luke Cooper/Hermione's ex-boyfriend
- Selena Gomez as Jamie Stein/Elise's best friend and Esther's new sister
- Lucas Till as Jake Lever/Elise's boyfriend who gets killed by Esther.
- Jamie Foxx as Detective Oscar Bennett/A detective who interviews Lucy, Hallie, Bea and Roxanne about Esther and how they become her foster sister and tried to kill their families.
- Amy Adams as Nina Stein/Jamie's mother and a widow.
- Rooney Mara as Nancy Lewis/A mysterious girl who knows about Esther.
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