In the luxurious setting of Beverly Hills, California, the affluent businesswoman Vivian "Viv" Ashe finds herself entrusting her pampered pet chihuahua, Chloe, to her rather irresponsible niece, Rachel, while she heads off on a ten-day business trip. During this time, Papi, the pet chihuahua of landscaper Sam, secretly harbors feelings for Chloe, who remains oblivious and somewhat repulsed by his affections. In a spontaneous decision, Rachel packs her bags for a trip to Mexico, bringing Chloe along for the ride. However, when Rachel leaves Chloe unattended in their hotel room to enjoy a night out, Chloe decides to search for her, only to fall victim to dog nappers who take her to participate in illegal dog fighting rings in Mexico City.
Once there, Chloe encounters a savvy street dog, a German Shepherd named Delgado. As Chloe finds herself slated for a battle against El Diablo, an intimidating Argentinean-Bolivian Doberman Pinscher, she is saved by Delgado, who ingeniously helps her escape from the horrific dog fighting scene by freeing other dogs and unlocking the cage. After much deliberation, Delgado decides that his priority is to return Chloe to Beverly Hills. Meanwhile, Rachel and Sam frantically seek help from the local authorities in Mexico, offering rewards to aid in the search for Chloe.
Their journey back home encounters several hiccups. Chloe and Delgado momentarily part ways while the latter goes to seek assistance. In the meantime, Chloe takes a moment to help a little pack rat named Manuel, saving him from the clutches of an iguana named Chico. Manuel, grateful for Chloe’s bravery, agrees to take Chloe's collar to a ship, hoping for the captain to assist her. Trusting Manuel, Chloe accepts his help but soon realizes she’s been tricked, as Delgado explains that iguanas are actually not carnivorous.
As the two dogs navigate their way back, they manage to hop a train, but their plans go awry when the conductor discovers them. They make their escape and wind up in the harsh Chihuahua desert, where Delgado shares his poignant backstory about being a former police dog who lost his edge after a confrontation with El Diablo. Just when things seem dire, they are rescued by a band of chihuahuas, led by a long-haired chihuahua named Montezuma. Montezuma imparts wisdom to Chloe, urging her to find her inner strength and recognize her potential, stating that chihuahuas may be small but are indeed formidable. Although offered a place among the group, Chloe declines, feeling a connection to home and a budding love for Papi, which she never fully embraced.
Meanwhile, Rachel and Sam scour Puerto Vallarta and discover that Chloe was seen in Chihuahua. As tensions rise, El Diablo manages to track down Chloe and attempts to capture her, but Papi swoops in for a heroic save, though he ends up imprisoned in an abandoned Aztec ruin. As Delgado pairs up with Manuel and Chico again with Chloe's collar, he realizes that despite being unable to track Chloe due to his sense of smell being compromised, he can still find her.
In a climactic battle, Chloe successfully rescues Papi, while Delgado faces off against El Diablo, ultimately defeating him. As Rachel reunites with Chloe, the authorities swoop in to apprehend Vasquez, the ringleader of the fighting operation. With all the chaos resolved, Chloe returns to her luxurious life in Beverly Hills, all without her owner, Vivian, ever being aware of the harrowing adventure she endured. Embracing a newfound romantic relationship with Papi, Chloe also celebrates the happy conclusion of Rachel and Sam's love story. As for Delgado, he returns to his roots as a police dog in Mexico, while El Diablo finds a new home with a wealthy adopter who has a penchant for stylish pets. Lastly, Manuel and Chico become prosperous in Beverly Hills, and Chloe and Papi embark on their first date, marking the start of new adventures yet to come.
