Scott and Lassie visit San Francisco's Chinatown. When Lassie is struck by a car while saving a child, she is taken to a vet's office. She may have amnesia so when a fire breaks out in the office, she escapes with no idea where she is or where she should go.
The next day Lassie searches for her identity. She visits a wax museum at Fisherman's Wharf and the waterfront, where she meets a down-on-his-luck young fisherman with a family and a boat loan he can't repay.
Lassie heads back into San Francisco over the Golden Gate Bridge and meets Sue, a lonely runaway. Next day Lassie brings together Sue with a lonely soldier. On her own again, Lassie is mistaken for a possibly-rabid collie named Tawny.
Her memory now recovering, Lassie flees through San Francisco streets while being hunted by both health officials and police as a rabid dog. Meanwhile Bob joins Scott in the search for their beloved collie.
Bob takes Lassie and Neeka, an Alaskan native, to see the cliff dwellings at Mesa Verde Park. While exploring Neeka falls, breaking his leg with Lassie going for help. A daring and dangerous rescue is conducted by the rangers.
Clint and Edie, along with Clint's guide dog Ginger, live in a remote area of the forest. Bob leaves Lassie for a visit so when Edie is injured Lassie leads Clint to her. Lassie goes for help while Ginger faces a mountain lion.
On a trip to survey tribal lands Lassie, Bob and a Navajo guide find and rescue a dog swimming in Lake Powell. Chuka is a lazy dog and would rather rest than tend sheep, but things change quickly when his owner is injured and Lassie must go for help.
Lassie and drifter Mark come upon a fire on the Pearson ranch, putting it out for which the Pearsons are grateful. Their collie Duke bonds with Lassie so Mark parts ways with his traveling companion. The dogs later tangle with a vicious stray.
Lassie finds happiness with Sgt. Hayes learning to herd sheep on his ranch. She has three pups with his collie Duke but the sergeant is under the mistaken belief a killer wild dog is the father. Lassie runs away to save her puppies.
After Lassie leaves the Hayes Ranch she finds shelter in a small cave with her pups but has no food or water. A young mute boy Kerry finds them, bringing them food but learns he is to be sent away to school. He then runs away.
The Holts and their friends search for the runaway Kerry but he is with Lassie and her pups. After a dangerous encounter with a mountain lion Kerry is found. Lassie leaves one of her offspring before continuing her journey.
Lassie's journey goes on, teaching the two pups about predators and survival in the wild. Taking shelter in an abandoned building during a storm, the adventuresome youngsters still find danger but Lassie keeps them safe.
Lassie and her pups meet Davey Braddock, a boy so grief-stricken by the recent death of his dog that he doesn't want anything to do with any other dog. Lassie and her pups have their work cut out for them.
Lassie and her remaining puppy meet a young teen Jodi Tyler in the forest. Living there with just her father, she has a special bond with animals. Lassie helps in a bulldozer accident then leaves her pup before continuing her journey.
Lassie befriends an elderly man who feeds a flock of birds and claims that they love him. His friends laugh at him about this claim, but when he becomes ill the behavior of the birds surprises everyone.
Lassie's journey is interrupted when she is sickened by insecticide. Found by Gary and his father, the collie regains her health on their horse ranch. She calms a nervous stallion, helps deliver a colt and fights a cougar.
Gary is upset over Glory's cougar injury and Lassie tries to comfort him. Bert is convinced to give equine surgery a chance so they follow the horse through the operation and swim therapy until he's ready to return to the track.
Lassie and a truck driver rescue a man walking across America while living "a year of Sundays." The workaholic trucker, who has been putting off a vacation, laughs at Mark's plan until a near-tragedy makes him re-think his own priorities.
During a storm Lassie takes shelter in a garage belonging to a lonely woman whose children have all gone. Lassie is dirty so the woman doesn't want to let her come into the house. Then the loose dirt behind her house begins to slide.