Vivian Ashe (Jamie Lee Curtis) leaves her pet chihuahua Chloe (Drew Barrymore) with her irresponsible niece Rachel (Piper Perabo). However, when Rachel decides to go to Mexico with her friends, Chloe gets dognapped. She is sent to the dog fights, and meets a German Shepherd named Delgado (Andy Garcia). Delgado helps her escape the dog fights and attempts to get her back to Beverly Hills. Meanwhile, Rachel is searching for Chloe with Sam (Manolo Cardona) and Papi (George Lopez), landscaper and dog before Aunt Viv gets home.

When Delgado was talking to his friend from when he was in the Mexican Police, Chloe encounters a pack rat named Manuel (Cheech Marin) trying to steal Chloe's diamond collar. She is tricked into giving him the collar, which was going to be used to get her home. When Delgado and Chloe were smuggled by a Coyote in a train, Delgado created a diversion so that Chloe wouldn't get caught by the train crew. But after Delgado jumped off the train, Chloe jumped with him, not wanting to abandon the truest friend she's ever found. When they walked across the Chihuahua Desert, Delgado told Chloe how he lost his sense of smell after being ambushed by El Diablo and his owner. El Diablo (Edward James Olmos), a fierce Argentinean mix Bolivian Doberman Pinscher, is sent by the dog fight ringleader to capture Chloe for the reward.

Later on, Manuel is seen with the collar by Delgado, so Manuel switches sides and helps Delgado find his sense of smell. Delgado sniffs the collar and gets his sense of smell back. He finds Chloe. Papi and Chloe try to escape from El Diablo, in which case Papi is placed in a cage. Chloe rescues him and finds her inner bark. However, El Diablo chases them. Delgado tries to save her, but Chloe jumps on El Diablo's back. She is thrown into a wall, which Papi thinks must have hurt her. Delgado finally evens out with El Diablo, after jumping on top of him. Chloe awakens and she retur

ns to Beverly Hills. Delgado gets a job with the police, and El Diablo runs away. Chloe and Papi go on a date by the gazebo and Chloe licks him on the face. Papi mentions that there might be a few miniature baby Chihuahuas in their futures. The two stray dogs that Sam and Rachel adopt on the trail of Chloe go to good homes too. El Diablo is adopted by a lady who has a passion for fashion. Sam and Rachel as well start to date.