Bolt (voice of JOHN TRAVOLTA) might not be a big dog, but he has super-canine powers that he puts to good use in battling the scheming villain, Dr. Calico (voice of MALCOLM McDOWELL), who repeatedly tries to kidnap Bolt's human, Penny (voice of MILEY CYRUS). Little does Bolt know, however, that his identity and entire experiences are just part of a TV show carefully constructed to prevent him from seeing any of the behind-the-scenes dealings.
Accordingly, when network executive Mindy (voice of KARI WAHLGREN) orders that the show's consistently happy endings - that don't sit well with adult viewers - be changed, the Director (voice of JAMES LIPTON) ends one episode with Calico successfully nabbing Penny. Thinking that's real, Bolt escapes but ends up knocked unconscious in a box that's shipped from Hollywood to New York City.
There, Bolt sets out to find Penny, but can't understand why his usual powers have disappeared. Even so, and thinking she works for Calico, Bolt kidnaps streetwise alley cat Mittens (voice of SUSIE ESSMAN) and the two set off on a cross-country trek back towards Los Angeles. Along the way, they pick up Rhino (voice of MARK WALTON), an overzealous hamster and huge fan of Bolt's who eagerly offers his assistance. From that point on, they race back to Hollywood, unaware that Penny's Agent (voice of GREG GERMANN) has replaced the missing star with a lookalike dog.