Teenager Grace MacLean (Scarlett Johansson) and her best friend Judith (Kate Bosworth) go out early one winter's morning to ride their horses, Pilgrim and Gulliver. As they ride up an icy slope, Gulliver slips and hits Pilgrim. Both horses fall, dragging the girls onto a road and colliding with a truck. Judith and Gulliver are killed, while Grace and Pilgrim are both severely injured. Grace, left with a partially amputated right leg, is bitter and withdrawn after the accident. Meanwhile, Pilgrim is traumatized and uncontrollable to the extent that it is suggested he be put down. Grace's mother, Annie (Kristin Scott Thomas), a strong-minded and workaholic magazine editor, refuses to allow Pilgrim to be put down, sensing that somehow Grace's recovery is linked with Pilgrim's.
In 1912, a teenage boy named Albert Narracott (Jeremy Irvine) from Devon, England, witnesses the birth of a Bay Thoroughbred foal and subsequently watches with admiration the growth of the young horse. Much to the dismay of his mother Rose (Emily Watson), his father Ted (Peter Mullan) buys the colt at auction, despite their needing a more suitable plough horse for the farm work. Albert's best friend, Andrew Easton (Matt Milne), watches as Albert teaches his colt many things, such as to come when he imitates the call of an owl by blowing through his cupped hands.
Three men, Red Pollard (Tobey Maguire), Charles S. Howard (Jeff Bridges), and Tom Smith (Chris Cooper) come together as the principal jockey, owner, and trainer of the championship horse Seabiscuit, rising from troubled times to achieve fame and success through their association with the horse.
The film starts with a brief introduction in the 19th-century American West featuring a bald eagle gliding over the homeland of the mustangs, showing several western US National Parks. There is then a scene showing the birth of a dun Kiger Mustang, Spirit. Spirit soon grows into a stallion, and assumes the role of leader of the herd, whose duty it is to keep the herd safe, demonstrated when he saves two foals from a mountain lion. Spirit is a courageous leader, but has great curiosity. Spotting a strange light one night not far from his herd, the stallion is unable to control his curiosity and moves towards it. To Spirit's surprise, he finds restrained, docile horses, and two-legs (possibly wranglers) sleeping around a campfire. They wake up, and seeing him as a magnificent specimen, chase and capture him, then drag him to a US cavalry post.
In 1891, American Frank Hopkins (Viggo Mortensen) and his mustang, Hidalgo, are part of Buffalo Bill's Wild West show, where they are advertised as "the world's greatest distance horse and rider". Hopkins had been a famous distance rider, a cowboy, and a dispatch rider for the United States government; in the latter capacity he carried a message to the U.S. 7th Cavalry Regiment authorizing the Wounded Knee Massacre of Lakota Sioux.
During a thunderstorm, a traveling circus accidentally leaves behind a baby zebra. The foal is rescued by widower Nolan Walsh, a former Thoroughbred-racehorse trainer who retired when his wife, a jockey, died in a racing accident. Nolan takes the zebra home to his farm and leaves it under the care of his daughter Channing "Chan" Walsh, who names him "Stripes". Stripes befriends the other farmyard animals, including Saanen goat Franny and Shetland pony Tucker. One day, he becomes convinced that he is destined for the nearby racetrack, the Kentucky Open, after watching a race, not realizing that he is a zebra and is not qualified to race.
Norman "Sonny" Steele is a former championship rodeo rider who has sold out to a business conglomerate and is now reduced to making public appearances to sell a brand of breakfast cereal. Prior to making a Las Vegas promotional appearance to ride the $12 million champion thoroughbred race horse who responds to the name of Rising Star, Sonny discovers to his horror that the horse has been drugged and is injured.
In 1969, Denver housewife and mother Penny Chenery (Diane Lane) agrees to take over her ailing father, Christopher Chenery's Meadow Stables in Doswell, Virginia, despite her lack of horse-racing knowledge. With the help of veteran trainer Lucien Laurin (Malkovich), Chenery navigates the male-dominated business, ultimately fostering the first Triple Crown winner in 25 years and one of the greatest racehorses of all time.
Alec Ramsey is aboard the steamer Drake off the coast of North Africa, where he sees a wild black stallion being forced into a makeshift stable and heavily restrained by ropes leading to his halter. Captivated by the horse, Alec later sneaks to the horse to feed him some sugar cubes, but he is caught by the horse's supposed owner, who tells him in Arabic to stay away from Shetan and shoves the boy away.
Alexandre Beck is a doctor who has slowly been putting his life back together after his wife Margot was murdered by a serial killer. Eight years on, Alex is doing well, until he finds himself implicated in a double homicide, which has plenty of evidence pointing to him as the killer – though he knows nothing of the crimes. The same day, Alex receives an email that appears to be from Margot, which includes a link to a surveillance video clip that features his late wife looking alive and well. The message warns Alex that they are both being watched. He struggles to stay one step ahead of the law, while henchmen intimidate Alex's friends into telling them whatever they might know about him – the henchmen eventually kill one of them, Charlotte. In the meantime, Alex's sister Anne persuades her well-off wife Hélène to hire a respected attorney, Élisabeth Feldman, to handle Alex's case.
In 1895, a young immigrant couple is refused entry into Manhattan because they have consumption. When their infant son is not allowed entry to the country without them, the couple place him in a model sailboat named "City of Justice," in which the baby floats to the New York City shoreline. In 1916, the baby boy has grown up to become Peter Lake (Colin Farrell), a thief raised by a supernatural demon posing as the gangster Pearly Soames (Russell Crowe). Peter is marked for death when he decides to leave Pearly's gang. In a confrontation, he is rescued by a mysterious (winged at times) white horse, his guardian angel.
Katherine "Katy" McLaughlin (Alison Lohman) has big dreams of administering her father's Wyoming horse ranch one day, but her father, Rob (Tim McGraw), has other plans. He is currently grooming her older brother, Howard (Ryan Kwanten), to take over the ranch and sends Katy away to an exclusive private school where she constantly feels like a misfit. Being a similar, independent spirit to Katy, Rob is having trouble understanding his daughter as she continually defies his authority to follow her own path. When she comes home for the summer, Katy is met with her father's disapproval because she did not finish a writing assignment at school, but is happily greeted by her mother, Nell (Maria Bello), and Howard. As much as Katy wants to run the ranch, Howard does not, and instead longs to attend college. One day while out riding, Katy finds a wild mustang, and feels an instant connection with the horse. She sets off to tame the mare, which she names "Flicka", despite her father's protests that he does not want a mustang near his horses.
When Jim Craig and his father Henry are discussing their finances, a herd of wild horses called the Brumby Mob passes by, and Henry wants to shoot the black stallion leader—but Jim convinces his father to capture and sell them. The next morning the mob reappears and Henry is accidentally killed. Before Jim can inherit the station, a group of mountain men tell him that he must first earn the right – and to do so he must go to the lowlands and work.
In 1949, young cowboy John Grady Cole's maternal grandfather dies. John had grown up on his grandfather's ranch, but it was put up for sale when the old man died. His mother has no ties to it anymore, and would rather have the money. With no home, John asks his best friend Lacey Rawlins to leave his family ranch in San Angelo, Texas and join him to travel on horseback to cross the border 150 miles south, to seek work in Mexico. They encounter a peculiar 13-year-old boy named Jimmy Blevins on the trail to Mexico, whom they befriend but from whom they then separate. Later on they meet a young aristocrat's daughter, Alejandra Villarreal, with whom Cole falls in love.