In Lonesome Dove, Texas former Texas Rangers Augustus 'Gus' McCrae and Woodrow F. Call are spending their time not doing much of anything. They have something of a reunion when old friends Jake Spoon and Joshua Deets arrive. They've not seen each other for something going on 10 years. Jake has an idea: they should round up a herd of cattle and drive them north where they could make their fortune. McCrae is a bit slow to come around the idea but they're soon crossing the border rustling horses and cattle that have been stolen by a Mexican bandit. By the time they're ready to set out, Jake Spoon has had a change of heart. He's been carrying on with Lonesome Dove's only saloon girl, Lorena Wood, and he's promised to take her to San Francisco. They're traveling more or less in the same direction so they're all going to be seeing each other quite a bit. The men on the cattle drive face long days and bad weather. One of them will not survive the first river crossing.

With the loss of Sean O'Brien, the cook refuses to cross the river and Woodrow and Gus find themselves in their old stomping grounds of San Antonio looking for someone to prepare their meals. On the trail, Jake Spoon abandons Lorena temporarily to go off gambling. Gus visits her but is far more concerned when an old foe, Blue Duck, appears. Blue Duck rides off but later returns and takes Lorena hostage. She has a very hard time of it. Meanwhile, Roscoe Brown is trying to catch up with July Johnson in Texas. He finds him but not before being joined by a young woman and coming face to face with two bandits. They all meet up with Gus and July helps Gus locate Lorena. It's not so good for those July's left behind at his own camp however.

Gus and Lorena rejoin the cattle drive. Elmira makes her way to Ogallala, with July close on her heels. Jake's new partnership doesn't turn out as planned.

Still on the trail, the men face ever increasing danger. They have an 80 mile stretch without water and the weather has turned with the onset of winter. Joshua Deets' encounter with a group of young Indians leads to tragedy. Similarly, Gus is severely wounded in an encounter with Indian warriors. He is rescued by mountain man but has to have his right leg amputated. By the time Call catches up with him, it's too late as Gus refused to let the doctor amputate his other infected leg. His dying wish is to be buried in Texas and Call promises to take him home. Newt knows that Call is his father but that's something Call has never acknowledged. He does began to test the boy and leaves him in charge after he proves his mettle. In the spring, Call begins his 3,000 mile journey home, keeping his promise to his friend.