Geraldine Brooks’s novel Horse opens in 2019 in Washington, DC. Art history graduate student Theo is working on an article when he notices a neighbor setting out “free stuff” on the curb. He sees a painting of a horse in the pile and, intrigued, takes it home. Jess is the manager of the Osteology Prep Lab at the Smithsonian’s Museum Support Center. A colleague calls asking her to find a nineteenth-century horse skeleton for a researcher.

The story now shifts to 1850. Thirteen-year-old Jarret is enslaved by Dr. Elisha Warfield at the Meadows in Lexington, Kentucky. Jarret’s father is Harry Lewis, a free man who has distinguished himself as a racehorse trainer. The mare Alice Carneal gives birth to a foal with four white feet who receives the name Darley. Harry is the one who convinced Dr. Warfield to bring together the mare and the winning stallion Boston in hopes that their offspring would be a great racehorse.

Back in 2019, Theo decides he wants to know more about the horse painting. He reflects on his own pleasure in horses and in playing polo. In 1850, another man also finds pleasure in horses. Thomas J. Scott is a painter who specializes in animal portraits and keeps a diary of his experiences at the Meadows. Scott and Jarret develop a tentative friendship, and Scott tells Jarret that Dr. Warfield plans to give Darley to Harry as his wages.

Jess discovers that the horse skeleton is in the Natural History Museum attic. Theo begins his research on the painting and is struck by a work from Edward Troye that shows Black people as individuals.

Jarret monitors Darley carefully and decides that he will raise the little horse to have a good temper. The bond between the two is already forming, and Darley is showing a unique personality and a strong physique.

Jess meets researcher Catherine Morgan, and the two study the horse skeleton. Catherine tells Jess that this is no ordinary horse but “the greatest racing stallion in American turf history.”

In 1852, Scott paints Darley and gives the picture to Jarret. Scott also meets Dr. Warfield's son-in-law, the abolitionist Cassius Clay, at an uncomfortable family dinner. Jarret has broken Darley, and the young horse is showing great promise. Harry has married and bought Beth but assures Jarret that he will still save for his son’s freedom.

Jess and Catherine analyze the horse’s skeleton further, and Jess looks at images of the animal. Jess decides that she can rearticulate the skeleton so that it better represents the horse’s true anatomy, and both women decide that there is plenty of room for deeper study.

The spring of 1853 brings Darley’s first race, and he wins both heats easily even after a false start. Richard Ten Broeck of New Orleans, owner of the Metairie race track, is present to inspect the young horses. Jarret rides out to the Meadows with him, and Ten Broeck questions him thoroughly.

As Jess is getting ready to return to her apartment, she mistakenly thinks that a Black man (who is actually Theo) is trying to steal her bike. The bike is his own; hers is on another rack. Jess is embarrassed. Back at the apartment, Jess and Catherine discuss the latter’s veterinary career in the racing world.

After Darley’s successful race, Dr. Warfield agrees to sell the horse to Ten Broeck and his associate Willa Viley. When Dr. Warfield hesitates because the horse truly belongs to Harry, the others remind him of the rules against Black men racing. The doctor’s reputation is at stake, and he decides to sell. Jarret is angry and determines to take Darley and ride away to freedom. Clay and his daughter, Mary Barr, intercept Jarret, and Ten Broeck buys the boy along with the horse.

Theo takes his painting to a conservationist, who cleans it and reveals that the horse has four white feet. Theo and Jess meet again, and Jess gives Theo a tour of the Museum Support Center. The conservationist also discovers that the artist who created the painting is Thomas J. Scott. The horse’s name is Lexington.

Jarret and Darley, now renamed Lexington, travel to Natchez, Mississippi, where they stay at the Fatherland plantation. Trainer Pryor separates Jarret from the horse, and the boy works in the smithy and in the fields. He learns much about what it means to be enslaved.

Lexington gets colic after eating too much grain, and Pryor calls Jarret to help. Jarret treats the horse and refuses to leave him again. The boy also decides that he must learn to read and write, and Uncle Jack gives him lessons. Ten Broeck sends for Jarret and Lexington to go to New Orleans so that the horse can race.

Theo and Jess discover that the museum owns another painting of Lexington that is part of the Martha Jackson Memorial Collection. The two are now developing a relationship. The story shifts to 1954, and Martha Jackson is watching Jackson Pollock paint. She has given up her own art to become a critic and gallery owner. Martha’s housekeeper, Annie, has a painting of a horse with four white feet that she wants to sell, and Martha agrees to look at it. Martha reflects on her mother, Cyrena, who was a champion jumper on Royal Eclipse until she fell, hit her head, and died in a freak accident.

Lexington, ridden by Henri Meichon, easily wins his first New Orleans race, and Jarret appreciates his new life at Metairie. Scott paints Lexington again and develops a relationship with a New Orleans painter named Julien. Viley is upset that Jarret is training Lexington but soon appreciates the young man’s methods.

Jess further examines the horse’s skull and sees a malformation in the bone beneath the eye. Catherine tells her that it was probably the result of an infection. Later, she notes that the horse likely gorged himself on grain at some point, with the food causing an infection that damaged a nerve. The relationship between Jess and Theo grows.

Lexington wins both heats of the Post Stakes but loses the rematch against Lecompte under mysterious circumstances. Jarret and the horse go north for further training. When the two return, Lexington is almost blind in one eye, but Jarret keeps it a secret. Lexington beats Lecompte’s record in the “Race Against Time.” He also wins in a rematch against Lecompte. Ten Broeck realizes that the horse is going blind and sends Jarret and Lexington to Robert Alexander in Kentucky.

Jarret has a great deal of authority on Alexander's farm by 1861. Lexington’s offspring are champions. Jarret is in a relationship with May, an enslaved woman whose husband has been sold south. The Civil War begins, and Scott enters the Union army.

Martha Jackson looks at Annie Hawthorne’s painting, which is one of Lexington by Scott. She ends up buying it.

May’s husband, Robert Hawthorne, returns and buys May and her son. Jarret gives them one of Scott’s paintings of Lexington. Scott paints the horse again, this time with Jarret in the portrait. Quantrill’s raiders attack Alexander’s farm and take Scott and several horses, but Jarret and Lexington rescue them and ride north to Illinois and safety.

Theo decides to return his valuable painting to the neighbor, but he is killed by police while trying to help an injured woman. Jess must identify Theo’s body. She decides to return to Australia after setting up a new exhibit in Kentucky with Lexington’s skeleton and Theo’s painting.

In 1875, Jarret travels to New York from his home in Canada to purchase the portrait Scott painted of Lexington and himself. He is a wealthy, successful, free man now and goes by the name of Jarret Lewis.