- Charlize Theron as Mary Peppers
- Carl Reiner as Mr. Bickenbach
- Betty White as Mrs. Pepperpot
- Oscar Isaac as Mr. Pepperot
- Carol Burnett as Mrs. Benedict
- Nick Kroll as Bill
- Chloë Grace Moretz as Abigail Bickenbach
- Finn Wolfhard as Jim Bickenbach
- Samuel Joslin as Georgia Bickenbach
- Mel Brooks as Uncle Arthur
- Will Ferrell as Warren "Winchell" Wallace
- Steve Coogan as Henry Goodman
- John C. Reilly as Thomas Freeman
- David Warner as Admiral Benson
- Stan Lee as Mary Pepper's parrot umbrella.
- Wallace Shawn as Shamus the Coachman Dog
- Brad Garrett as Gerry the Horse
- Kelsey Grammer as Wolf
- Keegan-Michael Key as Badger
- Jordan Peele as Weasel
- Kath Soucie as Lily
- Tara Strong, Grey DeLisle, Roger Craig Smith, Fred Armisen and Kate Miccuci as Mouse family
- Eric Bauza as Gumby the Cat
- There Are Some Things You Just Gotta Do - Mary Peppers
- F.A.N.T.A.S.T.I.C - Mary Peppers, Bill, and Mouse Family
- Mr. Moon - Mary Peppers
- Steal If You Need It - Mary Peppers and Bill
- Never Gonna Replace Me - Uncle Arthur and Bill
- A Whole New Life - Mary Peppers
- Mary Peppers Returns was the first Mary Peppers film to be filmed in Panavision (anamorphic) for the widescreen 2.39:1 aspect ratio and rated PG by the MPAA, unlike the original film that was rated G.
- Mary Peppers Returns is Shires's first live-action/traditional animated hybrid film since The Golden Tear.
- This film includes some hand drawn animation made by Shires Animation Studios, making it the first time since 2011's MegaGenie to use traditional hand drawn animation.
- The first Shires to use the short 2011 Shires closing logo, since The Unborn.
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