The action takes place in a little town called Lonesome Dove, where nothing extraordinary ever happens. The men who work at the Hat Creek Company spend their time looking for something exciting to do and waiting for lunch time when they all gather around and discuss. A few man named Augustus McCrae, Pea Eye, Newt Call and Gus all gather around to discuss at lunch time and their subject is Lorena, the town’s whore. Some of the men make fun of Gus, saying that Lorena wants to marry him and that he should be careful around her.
Later that day, Gus goes to Lorena and he pays her to tell him how she ended up a prostitute but she refuses to do it so Gus leaves. After that, Gus goes to the only saloon in town where he meets with a man named Boggett Dish who also is in love with Lorena. The two men talk and spend their night listening to music.
The next day, Dish is offered a job to go to Mexico to buy some horses. Dish agrees to go to Mexico and the man who was supposed to go with him, Deets, enters accompanied by a man named Jake. Jake was a former ranger who knew almost everyone in the little town. Jake was on the run because he killed a man and his destination was Montana, a place where he hoped he will find peace. Gus and Jake talk about Newt, a boy that was most likely fathered by Jake, and they Jake asks about the whore that lives in the town.
That afternoon, two men come to the Cattle Company looking to buy some horses. The men on the farm go looking for Call who promises the men 100 horses and so he calls for Dish to go and get him some horses from a rival Cattle Company. Dish is drunk but he still insists that he can carry the job so he is given a gun and told to go to Pedro Flores. Dish goes along with a large group of men, including Newt and Jake and some of the men in the groups are concerned that they should not be stealing from a dangerous and armed farmer. Newt is amazed to see the way the world looks outside his village.
The group stumbled upon two white men, Sean and Allen who lost their animals and ran out of food. Call offers to help the two men find their way back to a camp even though he initially wanted to rob them.
The men find two heard of horses that are unguarded and they quickly steal the horses and head back to Lonesome Dove without encountering any troubles on the way there. Call wants to sell the horses to Wilbarger but he refuses to buy them, claiming that he wants Call’s horse instead. Call refuses so Wilbarger leaves but not before telling Call to stay away from Montanan.
Lorena plans to leave the city with Jack with whom she had fallen in love with and she even gives up prostituting herself because of her love for Jack. Jack however has no intention of helping her and when other men try to warn Lorena about him she refuses to listen.
The two Irish boys found by Call began working for him, hoping that he will send them to Montana. After Call finds that his biggest rival died, he decides that he and all his employees should go to Montana and try their luck there.
Lorena realizes that Jack is not the man she thought him to be after Gus tells her that Jake will most likely go to Montana with the rest of the group and not to San Francisco where Lorena wanted to go. Gus invites Lorena to go with them as well and she tells Jake to take her with him. Jake tells Lorena that he will go to Montana and he slaps her when he finds that Gus paid Lorena for sexual favors. Jack buys Lorena a horse and Lorena sleeps one more time with the owner of the saloon but she hides it from Jack and keeps all the money the man gave her. Jack still hopes that Lorena will chose to remain behind that that doesn’t happen so the group and 2600 cattle begin their long journey north.
In chapter 26, the reader is told that Jack killed a man named Ben Johnson in Arkansas and that the victim’s brother decided to hunt down Jack and hang him for his crime. The sheriff, July, is pressured by Ben’s widow to go after Jake and even July’s wife tries to convince him to go and even take their son, Joe, with him. July leaves with Joe and he leaves his deputy behind, telling him to take care of his wife. Soon after that, the wife runs away and so the deputy, Roscoe, goes after July to tell him what happened.
The narrative moves back to the camp where a storm is approaching. The men endure the rain all night and in the morning they dry their clothes and then go on the road again. Scared by the storm, Jack tells the group that he wants to go to Saint Antonio. When Lorena refuses to go with him, he slaps her but the abuse does not affect her. On the same day, the group loses their first man, a boy named Sean who dies after being bitten by snakes.
The group continues traveling and Lorena realizes that she enjoys being on the road and that she would rather continue traveling than go with Jake. A man named Bolivar decides to go on his way as well and the group finds itself in the need of a cook and a wagon so they stop in San Antonio. They are unable to but they meet and Indian with whom Gus and Call had an altercation a long time ago. Gus warns Lorena about him before riding back to the main camp where he talks with Newt to protect Lorena. Newt returns in the middle of the night back to the camp to take care of the cattle and during that time the Indian kidnaps Lorena. He takes her to his friends and they all rape her and keep her tied up, without giving her any water to drink.
When the camp finds about her, only Gus decides that he must go and look for her while Jack goes into the next city, forgetting about Lorena.
Meanwhile, July and Joe find Rascoe and a woman who tagged along named Janey. The group then goes on searching for Jack and for July’s wife, Elmira.
Elmira ran away from her husband because she wanted to find her former lover, a man named Dee Boot. While her husband was looking for her, she was with a man named Big Zwey who developed an obsession with her. Elmira had no feelings for him however and she was only using him to find the one she lived.
Gus continued on his pursuit to find Lorena but one night he was found by a group of Indians. Gus killed the Indians and the next day he was found by July. The two talked and July offered to help Gus get Lorena back. Gus kills all the Indians in the camp and gets Lorena back but the Indian who kidnaped Lorena, Blue Duck, escapes. When Gus returns to his own camp, he finds his son, Rascoe and Janey killed by Blue Duck so he buries them with Gus’s help and decides to give up on hunting Jake and return home, to look for his wife.
Gus takes care of Lorena and nurses her back to health. They eventually catch up to the heard and Gus continues to take care of Lorena. After a few days of riding, the group finds that Jack Spoon is once more near their camp but none of them is happy to hear it.
After leaving the camp, Jack associated himself with the Suggs brothers and the three of them spend their days killing everyone who they meet and robing everyone.
Lorena gets close to Gus but he refuses to marry her but he still takes care if her.
Gus and Call realize that Jake is with the group of thieves that robbed the country and when they catch them, they hang them, including Jack. Before dying, Jack gives his horse to Newt who could not understand while Jack had to die as well.
Meanwhile, July continues to search for his wife and he stumbles into the house of a woman named Clara, Gus’s former lover. She tells him that his wife passed through there and that she gave birth to a son she left behind. Clara gives July the baby she has been taking care of and tells him that Clara went to the next city where her ex was being held in prison. When July arrives there, he finds that Elmira’s former lover was hanged so he plans to take her home. Elmira however is sure that she does not want to return with her husband so she convinces Zwey to run away together. They do not reach the next city however as they are both killed by Indians.
Clara convinces July to stay on her farm and take care of his baby and he decides to do just that when he realizes that he will never get his wife back. Clara is visited a few days later by Gus, Call, Newt and Lorena and she convinces Lorena to remain behind with her at the farm. The rest of the boys continue on their journey to Montana.
Deets die during an altercation with a tribe of Indians and his death affected Newt who wished he would have never left Lonesome Dove. The men reach Montana and Gus and Pea go to scout the area. They are quickly discovered by a group of Indians and Gus is hit with an arrow in the leg. Gus sends Pea back to the camp and when Call hears about what happened to Gus, he quickly goes to help him.
Meanwhile, Gus got out of the cave he was staying and managed to get to a village where he passed out. When he woke up, one of his legs was cut off and Call was near him, trying to convince him to have his other leg amputated as well. Gus refuses and knowing that he will die, he makes Call promise to tell Newt that he is his real father and to bury his body in a grove in Guadalupe. He also writes to letters, one for Clara and one for Lorena. Gus then dies with Call by his side.
Because of the weather, Call decides that he will return in spring with Gus’s body. He sets up camp in the North but he still refuses to tell Newt that he is his father. When spring comes and Call decides to go an burry Gus, he leaves his horse to Newt and then he left without uttering another word.
After months and months of traveling, Call finally reaches the place where Gus wanted to be buried and after he buried him, Call returned to his old farm, deserted now.