It is 1876. Captain Augustus "Gus" McCrae and Captain Woodrow F. Call, two famous ex–Texas Rangers, run a livery called the Hat Creek Cattle Company and Livery Emporium in the small dusty Texas border town of Lonesome Dove. Smooth, charming and easy going, Gus loves women and women return the sentiments, but he's twice a widower and he never marries the love of his life, Clara. Although he had proposed many a time, she had rejected him every time because, in her words, Gus is "a rambler," and she despises Call because she feels jealous of the years Gus spent with him instead of her. She needed to settle down and have a family and a good life; he was brave and a dead aim, but was lazy and prone to wandering away for another adventure.
While McCrae is warm, good natured, and understanding of people, Captain Call, Gus's best friend and partner, is the opposite: a workaholic taskmaster who hides in his work, emotionally cut off. He is afraid "to admit he's human," according to McCrae. He loved only one woman, a prostitute named Maggie, who gave birth to a son, Newt. Though both Call and McCrae know (or at least strongly suspect) who Newt's biological father is, Call refuses to admit it and give Newt his name. He is hypercompetent at his work to compensate for his complete failure at human relationships. He is cold and driven by pride and honor, not love. Even when he drags the body of the only human who ever understood him and loved him anyway over 2000 miles across the Great Plains, suffering ridicule and hardship, he claims he is doing it for duty, not friendship. He is the Western version of Captain Ahab whose reckless stubbornness ends in tragedy.
Working with them are Joshua Deets, who is an excellent tracker and scout from their Ranger days, Pea Eye Parker, another former Ranger who works hard but isn't all too bright, and Bolivar, a retired Mexican bandit who is their cook. Also living with them is the boy Newt Dobbs, a seventeen-year-old whose mother was a prostitute named Maggie and whose father may be Call.
The story begins in the small town of Lonesome Dove, as Jake Spoon, a former comrade of Call's and McCrae's, shows up after an absence of more than ten years. He is a man on the run, having accidentally shot the dentist of Fort Smith in Arkansas. The dentist's brother happens to be the sheriff, July Johnson. Reunited with Gus and Call, Jake's breath-taking description of Montana inspires Call to gather a herd of cattle and drive them there, to begin the first cattle ranch in the frontier territory. Call is attracted to the romantic notion of settling pristine country. Gus is less enthusiastic, pointing out that they are getting old and that they are Rangers and traders, not cowboys. But he changes his mind when Jake reminds him that Gus' old sweetheart, Clara, lives on the Platte, 20 miles from Ogallala, Nebraska, which is on their route to Montana. Captain Call prevails. They make preparations for their adventure north, including stealing horses in Mexico and recruiting almost all the male citizens of Lonesome Dove.
Ironically, Jake Spoon decides not to go after all, being selfish and undependable and because he promises the town's only prostitute, Lorena Wood, known as Lorie, he'll take her to San Francisco.
Ogallala also happens to be the destination of Elmira, the wife of Sheriff Johnson, as she runs away to meet up with her true love, Dee Boot. So the three groups head north. They encounter horse thieves, murderers, hostile Indians, inclement weather, and a few inner demons.