Lonesome Dove is divided into three parts. Part I takes place in Lonesome Dove, a small border town near the San Antonio River that gives the novel its title. Nothing extraordinary ever happens, but that does not prevent former Texas Ranger Woodrow Call from making nightly patrols at the river. While Call is restless in his retirement, his friend and business partner Augustus McCrae enjoys a leisure lifestyle. Augustus spends his time drinking, gambling, sitting and watching the sunset, visiting Lorena (a local sex worker), and making sourdough biscuits. The men who work at the Hat Creek Cattle Company & Livery Emporium (including Pea Eye and Newt) do physically laborious tasks such as digging wells and training horses, all under Call's command. Bolivar, the cook, enjoys whacking the dinner bell every night, much to the annoyance of the others.
Augustus visits the Dry Bean saloon, where he finds Lorena, Xavier (the proprietor), Lippy (the resident piano player), and a cowhand named Dish Boggett. The next day, Call offers Dish a job, and Dish agrees. Deets, another former Ranger, returns from his trip to the bank accompanied by a man named Jake Spoon. Jake (also a former Ranger) knows almost everyone in the outfit. His horse's rough condition makes it clear that he rode hard, and sure enough, he admits to being on the run due to having killed a man. Jake mentions Montana, which intrigues Call.
That afternoon, two men come to the ranch looking to buy some horses. Call promises to have a hundred horses available the next day. He organizes a raid that night to Pedro Flores's Hacienda to steal the horses. Dish shows up drunk and lovesick, but he insists that he can carry out the job. That night, Call, Augustus, Deets, Dish, Pea Eye, and Newt ride out and succeed in getting the horses. They also find two Irishmen who accompany the group back to Texas.
Call returns Wilbarger's stolen horses and refuses to sell the prized mare named Hell Bitch. After forming a relationship with Jake, Lorena gives up sex work and tries to get Jake to take her to San Francisco. Jake has no intention of helping her and when other men try to warn Lorena about him, she refuses to listen. After Call finds out that Pedro Flores (his biggest rival) has died, he makes up his mind to go to Montana and try their luck there.
Augustus tricks Lorena into giving him a "poke" (sleeping with him) for $50. Jake finds out and slaps Lorena, but they still depart and travel at a distance from the main group. Before Lorena leaves, Xavier begs her to marry him but she refuses. Still, he pays her an exorbitant amount of money for a poke. This time, Lorena hides it from Jake. The outfit begins their journey driving 2,600 cattle northward.
Chapter 26 begins Part II of the novel from Sheriff July Johnson's perspective. After Jake Spoon kills July's brother, July's sister-in-law (named Peach) pressures him to go after Jake. July’s wife, Elmira, makes July her son, Joe, with him. July leaves with Joe and he leaves Deputy Roscoe behind with the request to look after Elmira. Soon after that, Elmira runs away and Peach pressures Roscoe to go 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 long. Jake wants to go to Saint Antonio to gamble. When Lorena refuses to go with him, he slaps her but the abuse does not affect her. On the same day, Sean O'Brien is attacked by water moccasins while crossing the Nueces River. He becomes the first person in the group to die.
The group continues traveling and Lorena realizes that she enjoys being on the road. Deets, who often scouts ahead of the outfit, stops by Lorena's camp to assist her and teach her how to do the chores that Jake neglects. Elmira takes a whiskey boat and discovers that one of the men (named Big Zwey) has laid claim to her. Roscoe meets a woman farmer named Louisa who proposes to him and later forces herself upon him. Rather than marry her, Roscoe continues traveling in search of July.
Bolivar falls asleep driving the wagon and accidentally shoots his gun, scaring the animals. The wagon crashes, nearly killing Lippy. As a result, Bolivar decides to return to Mexico. The group finds itself in the need of a cook and a new wagon, so they stop in San Antonio. Augustus breaks the nose of a bartender who insults him. Call and Augustus purchase a new wagon and two mules.
Roscoe is joined by a young girl named Janey, who escapes an abusive situation to travel with Roscoe. Still in need of a cook, Call and Augustus go to San Antonio. On the way, Augustus stops at a creek where he and Clara used to picnic together. They discover that Jake left Lorena to go gamble in San Antonio, so Augustus stays with her. A Native man named Blue Duck appears. Augustus urges Lorena to camp closer to the outfit for protection since Blue Duck is a known outlaw. When Lorena refuses, Augustus resolves to send Newt over to keep watch.
Call hires a new cook named Po Campo. Lorena refuses to be guarded by Newt, who secretly stays close by until the cattle stampede and separate Newt from his horse. During this time, Blue Duck kidnaps Lorena. Jake returns drunk and argues with Dish. Call is disgusted by Jake's behavior and kicks him out of camp. Augustus immediately takes off to rescue Lorena. Meanwhile, Blue Duck binds Lorena and travels extremely hard. Once they arrive at Blue Duck's camp, he sells her to his gang of men who take turns raping her.
July receives a letter from Peach in Fort Worth informing him about Elmira's disappearance. He switches tracks and starts searching for Roscoe instead of Jake. A group of bandits accosts Roscoe and Janey throws rocks from a distance until they capture her. July arrives and saves Roscoe. They all ride to Fort Worth before heading out to search for Elmira. Elmira is determined to find her former lover, a man named Dee Boot. She decides to use Big Zwey's obsession with her to get to Ogallala, where Dee is. They travel with a gambler named Luke.
Augustus continues on his pursuit to find Lorena, who is experiencing extreme trauma at the hands of her captors. Augustus has a shoot-out with the Kiowas who attack him under Blue Duck's instruction. After being forced to kill his horse for cover, Augustus craves company. July and his party come across the Kiowas and shoot at them. Later, Augustus and July confront the men at the camp where Lorena is held hostage. Augustus kills everyone there and rescues Lorena. Blue Duck escapes and kills Joe, Roscoe, and Janey, which devastates July. After burying all the dead, July goes off to Kansas to look for Elmira while Augustus and Lorena head back toward the outfit.
Augustus takes care of Lorena and nurses her back to health. They encounter Wilbarger, who supplies them with food and a tent. The outfit eventually catches up, but Augustus and Lorena travel at a distance due to Lorena's trauma around men. Bill Spettle is struck by lightning during the intense storms. The crew is assaulted by hail as they cross a river.
Call decides not to defend Jake against July since Jake abandoned Lorena and returned to gambling full-time. He consorts with sex workers and eventually goes to Dallas, where he falls in with the Suggs brothers and their accomplice Frog Lip, who are all outlaws. July continues riding in search of Elmira, and only the duty of telling her about Joe's death keeps July from committing suicide. Meanwhile, Luke harasses and attempts to assault Elmira, causing Zwey to smash his head in. Elmira nurses Luke back to health and the three continue traveling.
Augustus takes care of Lorena, who fears that he will abandon her. They take cover from a swarm of locusts. When Newt is again separated from the others, a group of Native men guides him back toward the outfit.
Jake regrets allying himself with the Suggses and Frog Lip, and waits for his chance to break off from the group. The group assaults various individuals and parties, including Wilbarger.
While in Dodge City, July finds out from an old acquaintance of Elmira's that Dee is still alive. Elmira's old friend, another sex worker named Jennie, tells July he should return home. However, July persists in searching for Elmira.
Lorena decides that she will try to marry Augustus before they reach Ogallala, where Clara lives. Deets and Call figure out from horse tracks that Jake is traveling with murderous outlaws.
Frog Lip dies as a result of the confrontation between the Suggses and Wilbarger. Dan Wilbarger murders and mutilates the corpses of three farmers. Deets finds Wilbarger and brings Call and Augustus over to sit with the dying man. Dish cares for Lorena while Augustus is away. As Newt and Pea Eye guard their horses, Call, Augustus, and Deets confront the Suggses and Jake. They hang the Suggses, and Jake spurs his own horse forward with a noose around his neck, effectively sparing the others from killing him. Before he dies, he gifts Newt his horse and saddle.
Chapter 75 begins Part III of the book from Clara's point of view. She cares for her comatose husband (who was kicked in the head by a horse) while running the household and horse business with the help of a man named Cholo. Elmira and Zwey show up at Clara's ranch, and Elmira soon gives birth to a baby boy. Shortly after, she departs for town in search of Dee. Zwey carries Elmira (greatly weakened after giving birth) to the town jail to speak with Dee. Dee is set to be hanged for accidentally killing a boy.
July suffers a snake bite but survives to reach Clara's house. Clara quickly realizes that July is the father of the baby that Elmira left behind. Elmira wakes to find herself undergoing treatment by a doctor. After Dee's death, Elmira has lost the will to live, but Zwey and the doctor nurse her back to health. July finally finds Elmira, but she clearly demonstrates her distaste for him by refusing to acknowledge his presence. Once he leaves the room, Elmira commands Zwey to take her to St. Louis.
July's depression and passivity annoy Clara. She cares for July and assigns him tasks around the ranch, but she also directly confronts him about his plans. Clara desires to raise the boy, who she has named Martin. She suggests that July stay and work at the ranch so as to play an active role in raising Martin.
As they get closer to Clara's residence, Augustus assures Lorena that he will bring her to Clara's house and introduce her to his former love. A rude cavalry captain named Weaver informs the outfit that Elmira and Zwey died at the hands of Sioux warriors. Weaver also tries to take some of the outfit's horses, but Call and Augustus refuse.
In Ogallala, the men take turns enjoying themselves in town. Augustus goes to buy new clothes for Lorena. When Newt, the Rainey brothers, and Pea Eye go to town, they have a violent run-in with men from the army. This enrages Call and he beats a man named Dixon nearly to death. Augustus gives the younger men some money to spend with prostitutes, and some of them use it to lose their virginity.
Augustus, Call, Lorena, and Newt go to Clara's household. Clara is thrilled to see Augustus, and she organizes a picnic. She also treats Lorena kindly, but expresses her distaste for Call. She refuses to negotiate her prices while selling horses and scorns Call for not claiming Newt as his son. After the picnic, Clara proposes that Lorena stay in her household and informs Augustus that she will never marry again.
Augustus, Call, and Newt return to the outfit, and they travel through an extremely dry section of land. Deets later dies during a misunderstanding with a young Native man. His death greatly affects Newt. Most of the outfit members grieve Deets's death and fear what they could face on the trail ahead. The outfit finally passes into Montana. When Pea Eye and Augustus scout the terrain ahead of the outfit, they have a violent altercation with a group of Native men that leaves Augustus with an arrow wound in his leg. Pea Eye returns to the outfit to get help. When Call finally finds Augustus in Miles City, it is clear that Augustus will soon die. The alcoholic doctor there amputated one of Augustus's legs, but Augustus refuses to let him amputate the remaining leg despite the clear indication of blood poisoning. Before he dies, Augustus writes letters for Call to deliver to Clara and Lorena, wills his half share of the cattle profits to Lorena, and requests that Call bury his body back near Lonesome Dove. Call makes arrangements to store Augustus's body for the winter, and he makes his way back to the outfit having lost his sense of drive and purpose.
Once the outfit arrives at the Milk River close to Canada, Call finally stops and they start constructing infrastructure for the ranch. A blizzard motivates the men to quickly build a log house. Dish collects his wages and heads back to Nebraska.
Meanwhile, Bob dies and July finds himself hopelessly in love with Clara. Dish arrives with the news of Augustus's death, and Lorena falls into a deep depression. Call arrives at Clara's ranch, having left Newt in charge of his own ranch in Montana. Clara disapproves and scorns Call for leaving Newt without verbally claiming him as his son.
On the trail, Call hears about Blue Duck's capture and rides to Santa Rosa to witness the hanging. Blue Duck chooses a murder-suicide (killing himself and a deputy).
Call finally reaches the spot where Augustus requested to be buried. He digs a grave and marks the spot with Augustus's old sign for their ranch. When Call returns to the abandoned ranch in Lonesome Dove, he finds Bolivar whacking the dinner bell. The Dry Bean is gone, and someone informs Call that Xavier burnt the establishment to the ground while still inside due to Lorena leaving. The novel ends here.
