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The interrelated short stories in Love Medicine span half a century, with various narrators taking turns telling the stories. In 1934, Marie Lazarre, age fourteen, leaves home to live at Sacred Heart Convent, a school on a hill in town. A perverted nun, Sister Leopolda, considers Marie evil and tortures her, culminating in scalding her with boiling water and stabbing her hand with a fork. As Marie flees, she runs into a boy named Nector Kashpaw who thinks Marie has stolen from the convent. Nector, good with money, thinks he might get a reward if he catches Marie. They argue, tussle, and have sex. Marie and Nector go on to have a long marriage, many children, and many challenges. These events happen in “Saint Marie” and “Wild Geese.”

In “The Beads,” it is 1948 and nine-year-old June Morrissey comes to live with Marie and Nector Kashpaw after her mother dies in the woods. Filthy and malnourished, June thrives under Marie’s care. A child of the woods, June grows close to her Uncle Eli, a recluse, and goes to live with him.

Three stories—“Lulu’s Boys,” “The Plunge of the Brave,” and “Flesh and Blood”—are narrated in 1957, but each offers events and details from both the past and present. Lulu Lamartine’s husband, Henry, dies when a train hits his car, and Lulu has sex with Henry’s brother, Bev, resulting in the birth of their son, Henry Junior. Several years later, Bev visits Lulu to claim Henry Junior as his own, but he falls in love with Lulu despite his marriage to Elsa. 

In “The Plunge of the Brave,” Nector Kashpaw narrates his story, beginning in the 1930s. As a young man, he played in Hollywood Western films and modeled for a famous painting called The Plunge of the Brave. After marrying Marie, seventeen years go by, filled with babies, drinking, gambling, work, and tribal leadership. In 1952, Nector realizes that he still pines for Lulu, whom he loved as a teenager. He reconnects with her and they make love, leading to weekly trysts for five years. When Nector decides to leave Marie, he pens two letters. The letter to Lulu accidentally leads to burning Lulu’s house down when Nector lets a lit cigarette ignite it. On the same day, in “Flesh and Blood,” Marie discovers the letter saying that Nector is leaving her for Lulu. Marie finds the letter in her kitchen after she visits the dying Sister Leopolda. However, when Nector later returns home, Marie realizes that he is staying and hides the letter again without mentioning that she found it in the first place.

Lyman Lamartine narrates “The Red Convertible” in 1973, but the story begins in 1970 when Lyman and Henry Junior buy a red convertible and go on a road trip to Alaska. When they return, Henry Junior is drafted and ends up in a Vietnamese prison, returning with post-traumatic stress disorder (PTSD). Before he goes home, Henry Junior meets young Albertine Johnson in Fargo. They have sex, but Henry Junior gets drunk and loses his senses. He explodes, screams, and weeps as “The Bridge” ends. Back at home, Henry Junior is jumpy and mean. Lyman deliberately damages the convertible to give Henry Junior a reason to live as he hoped Henry Junior would be interested in repairing the car. However, when the brothers drive to the Red River, they drink too much, Henry Junior turns morose, and they fight. After Henry Junior jumps into the river and drowns, Lyman pushes the car into the water and watches it sink.

The next cluster of stories are narrated from 1980 to 1984. Albertine Johnson and Dot Nanapush work at a truck weighing station together in “Scales.” Gerry, Dot’s husband, escapes from prison but is arrested again. Dot gives birth to their daughter, and Gerry is sent to a maximum-security prison for shooting a state trooper. June Morrissey dies on Easter Sunday while walking in the snow after a sexual encounter. Her niece, Albertine, goes home a week after her funeral and witnesses a violent night of drinking and fighting that involves King, Lynette, Marie, Nector, Lipsha, Gordie, and baby King Junior. Gordie, who has been separated from June for some time, starts drinking heavily, feeling guilty and responsible for her death. He hallucinates visits from June, lost in a fog of alcohol-induced psychosis. When Gordie hits a deer in “Crown of Thorns,” he thinks he has hit June. He goes to the convent to confess “killing his wife” and meets Sister Mary Martin who sees the deer in the backseat of the car, not a woman. 

The final cluster of events focuses on Lipsha Morrissey who was adopted by Marie and Nector as a young child. Lipsha carries magic in him and has a healing touch. He serves as an attendant in the Senior Citizens home, now the residence of Marie, Nector, and Lulu. Lipsha walks in on Lulu and Nector having sex in the laundry room, indicating that Nector still lusts for her. Lipsha agrees to help Marie reclaim Nector’s heart with “love medicine.” When he misses shooting wild geese to use their hearts for the medicine, he buys frozen turkeys as a shortcut. However, Nector chokes and dies when he eats the turkey heart. Family and friends attend Grandpa Nector’s funeral, and Nector’s spirit visits Marie. Lipsha explains to Marie that Nector loved her and releases the man’s spirit. Despite Lulu’s affair with Nector, Marie and Lulu become friends when Marie agrees to help Lulu recover from eye surgery. 

In the final story, Lulu tells Lipsha who his biological parents are: his mother was June Morrissey and his father was Gerry Nanapush. Lipsha journeys to a border town where he joins the army and envisions that Gerry will escape prison yet again. He leaves the army and drives to see King, whom he now knows is his half-brother, and finds him with Lynette and King Junior. As the men play poker, the TV announces Gerry’s escape. Gerry soon appears because King snitched on him while they were in prison and he’s angry about it. When the police show up to arrest Gerry, he escapes. After Lipsha demands King’s car, which Lipsha won in a game of poker, he discovers his father, Gerry, in the trunk. Lipsha helps Gerry cross the border and escape the police. After, Lipsha accepts who he is and emotionally releases his parents while standing on a bridge over a river, ready to return to the reservation.

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