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Newbern began voicing Sephiroth in the English version of Kingdom Hearts II. He later reprised the role of Sephiroth in the English-language releases of Final Fantasy VII Advent Children, Crisis Core: Final Fantasy VII, Dissidia: Final Fantasy, Dissidia 012 Final Fantasy, and Dissidia Final Fantasy NT.

George is best known for his roles as Charlie in the ABC show Scandal and Bryan MacKenzie in Father of the Bride and its sequel Father of the Bride Part II as well as Danny (The Yeti) in Friends and his recurring role as Julia's son Payne in Designing Women.

As a voice actor, George is known for providing the voices of Superman in many pieces of DC Comics media (most notably the Justice League and Justice League Unlimited animated series and the Injustice video game series). He voiced Superman in the game Injustice: Gods Among Us and its sequel. Newbern also voiced several characters in Star Wars: The Old Republic.

In the 80s, George had a recurring role as Payne McElroy, the son of designer Julia Sugarbaker, on the series Designing Women. He has since guest-starred on television in such series as Providence, Chicago Hope, Friends, Bull, CSI, Medium, Ghost Whisperer, Touched by an Angel, Criminal Minds, and Private Practice. He has a recurring role as a former CIA operative in Scandal.

Newbern's film credits include Adventures in Babysitting (1987) with Elisabeth Shue; Double Switch (1987); Switching Channels (1988) with Kathleen Turner, Burt Reynolds, and Christopher Reeve; and Father of the Bride (1991) and its sequel Father of the Bride Part II. In 2009, he appeared in Locker 13.