Chance (voiced by Michael J. Fox), an immature and disobedient American Bulldog and the narrator of the film, explains that he is the pet of Jamie Burnford (Kevin Chevalia), but expresses no interest in his owner or being part of a family. He shares his home with Shadow (voiced by Don Ameche), a wise old Golden Retriever owned by Jamie’s brother Peter (Benj Thall), and Sassy (voiced by Sally Field), a smart-mouthed Himalayan cat owned by Jamie and Peter’s sister Hope (Veronica Lauren). That morning, the children’s mother, Laura Burnford (Kim Greist), marries Bob Seaver (Robert Hays), and Chance manages to cause chaos by digging into the wedding cake in front of all the guests.
Shortly after the wedding, the family has to move to San Francisco because Bob must temporarily relocate there for his job. They leave the pets at a ranch belonging to Kate (Jean Smart), Laura’s college friend. Shadow and Sassy start missing their owners immediately, but Chance sees it as an opportunity to explore and have fun. Later in the week, Kate goes on a cattle drive, leaving the animals to be looked after by her neighbor Frank (Gary Taylor). However, half of her message to him is lost, leading him to believe that she has taken them along, leaving the animals alone. Worried by the disappearance of their host, the animals fear they have been abandoned. Shadow, refusing to believe that his boy would abandon him, resolves to make his way home. Not wanting to be left alone on the ranch, Chance and Sassy decide to accompany Shadow on his journey.
They head into the rocky, mountainous wilderness of the Sierra Nevada with Shadow leading by instinct. After a night spent in fear of the woodland noises, the group stops to catch breakfast at a river. However, two black bear cubs bother Chance and a large brown bear causes the group to flee. At another river, Sassy refuses to swim across to follow the dogs and instead tries to via a wooden path further downstream; halfway across, the wood breaks and she falls into the river. Shadow tries to save her, but she goes over a waterfall to her apparent death. Devastated, Shadow and Chance go on without her. Unknown to them, Sassy survives and is later found on the riverbank by an old man named Quentin (William Edward Phipps), who nurses her back to health.
Over the next two days, Shadow and Chance try unsuccessfully to catch food and encounter a mountain lion, which chases them to the edge of a cliff. Shadow gets an idea to use a balanced rock shaped like a seesaw as a way to thwart the mountain lion. While Shadow acts as bait, Chance pounces onto the end of the rock and sends the mountain lion over the cliff and into a river. Sassy hears the dogs barking in celebration and follows the sound to rejoin them.
The animals continue on their way, but Chance tries to befriend a porcupine, ending up with a load of quills in his muzzle. The animals then encounter a little girl named Molly (Mariah Milner), who is lost in the woods. Too loyal to ignore her, they stand guard over her and keep her warm during the night. In the morning, Shadow finds a rescue party and leads them back to the girl. They recognize the animals from a missing pets flyer and take them to the local animal shelter, but Chance mistakes it for a dog pound and the trio panic. As the medical staff removes the quills from Chance’s muzzle, Sassy sneaks in and frees Shadow. Together, they retrieve Chance and escape the shelter, unaware that their owners are on their way to get them.
Finally reaching their hometown, the animals cross through a train yard, where Shadow falls into a muddy pit and injures his leg. Demoralized, he tells Chance and Sassy to go on without him. Near dusk, Chance and Sassy finally make it home and are happily reunited with their owners. Shadow initially fails to appear, but eventually he limps into view and happily comes running home at the sight of Peter. Chance narrates how it was Shadow’s belief that brought them home and how the years seemed to lift off of him, making him a puppy again as he reunited with his boy. The film ends with Chance musing about how he truly feels “home” with his family, before happily running into the house at the smell of food.