* Russell Brand as Dr. Nefario, Gru's elderly, hearing impaired scientist assistant. It is hinted that he is Gru's father, but Gru only refers to him as "good friend."
* Elsie Fisher as Agnes, the youngest girl of the group of orphans. She is known for being addicted to unicorns and likes Gru from the start
* Dana Gaier as Edith, the middle girl of the group of orphans. She likes gross things and wears a pink beanie. She is the only one of the girls to think that Vector's and Gru's inventions and weapons were "cool"
* Miranda Cosgrove as Margo, the oldest girl of the group of orphans. She is, for a majority of the film, untrusting of Gru. But she later learns to grow close to Gru and her sisters feel the same way
* Julie Andrews as Gru's mother. In several of Gru's flashbacks, he showed her his plans to go to the moon, but she ignores everything he said
* Will Arnett as Mr. Perkins, the president of the Bank of Evil, Vector's father, and the film's secondary antagonist.
* Kristen Wiig as Miss Hattie, mistress of a local orphanage, Miss Hattie's House of Girls. For the most part she seems to hate her job and sees the girls more as an irritation than anything else
* Pierre Coffin as Tim / Bob / Mark / Phil / Stuart, five of Gru's minions
* Chris Renaud as Dave, one of Gru's minions who fired a missile launcher during the minion gathering
* Ken Jeong as Talk Show Host
* Danny R. McBride as Fred McDade, Gru's next door neighbor
* Jack McBrayer as Tourist Father / Carnival Barker
* Mindy Kaling as Tourist Mother
* Jemaine Clement as Jerry, one of Gru's minions
* Rob Huebel as Anchorman / Newscaster
* Ken Daurio as Egyptian Guard
* Philip Mathew as Second Egyptian Guard and himself
* Additional Voices as all of Gru's minions
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