Love Medicine is a novel composed of several interrelated short stories. The primary characters live on a Chippewa reservation in North Dakota. The novel spans the years 1934-1984 and depicts the characters at different times in their lives.
In "The World's Greatest Fisherman", the novel opens with the death of June Morrissey in a snowstorm. June's family comes together after the funeral, but not without conflict. Albertine Kashpaw arrives late because her mother did not want to disturb her studies by telling her about June's death. June's son King is also there with his mistreated wife Lynette and their neglected baby son. Albertine's sensitive cousin Lipsha arrives somewhat late, and the two of them look at the Northern Lights together.
Two subsequent stories, "Saint Marie" and "Wild Geese", focus on Marie, a young girl who wants to join the local convent. Her sponsor Sister Leopolda welcomes her with a violent love, eventually culminating in a physical fight that leave Marie with a stigmata-like scar on her hand. Later on, Marie escapes the convent and bumps into Nector Kashpaw. They have a sexually charged meeting, which leads to love and marriage.
In "The Island", Lulu Lamartine, the girl Nector spurned for Marie, moves in with Moses Pillager, the local hermit and medicine man. Moses is closed off and mystical, but he and Lulu fall in love on his private island and live together for years. She eventually becomes pregnant with their first child.
In "The Beads", Marie remembers when the young June first came to live with her. June's mother had died and June was discovered in the woods, starving and wild. Marie took her in and loved her, but eventually June moved out to live with Nector's brother Eli, a quiet and reclusive man after her own nature.
In "Lulu's Boys", Lulu's life as a mother is revealed. Her husband Henry dies, and she has a brief affair with Henry's brother Beverly, who fathers one of her sons. Years later Beverly comes back to reclaim his son, but ends up falling in love with Lulu instead.
"Plunge of the Brave" and "Flesh and Blood" focus on Marie and Nector's life together. In the former, Nector talks about his long marriage to Marie and his sudden midlife crisis; during this unsettling period, he initiates an affair with Lulu. When Lulu tells Nector that she is marrying Beverly, Nector burns her house down - but not before writing a letter to Marie saying that he is leaving her for Lulu. In the next chapter, Marie recounts her final confrontation with Sister Leopolda and her subsequent return home to find the letter. She never tells Nector that she saw it, and he does not end up leaving her for Lulu.
"A Bridge" and "The Red Convertible" tell the story of Henry Junior and Lyman, half-brothers and Lulu's sons. These two men were best friends growing up, but Henry Junior goes to Vietnam and comes back a shell of his former happy self. He becomes an alcoholic and has sex with an underage Albertine, who has run away from home. Lyman tries to raise Henry's spirits by getting him to fix up their old convertible, but Henry dies of drowning soon after the car is repaired.
In "Scales", Albertine spends a summer working at a truck weighing station with Dot Adare, the wife of the career criminal and local hero Gerry Nanapush. Gerry is famous for repeatedly breaking out of jail and he breaks out in time for Dot to go into labor, but has to flee the hospital when the police arrive on the scene.
In "Crown of Thorns", June's ex-husband Gordie Kashpaw falls into a deep depression after June's death. One night he sees a hallucination of her in his house and starts driving away, drunk. He hits a deer and puts it in the back seat of his car. But the animal is not dead: it wakes up, and in a panic Gordie kills it. He then hallucinates that he had killed June. He drives to the local convent and wakes up a nun and tells her he killed June. By morning, police have come to take the distraught Gordie away.
The title chapter, "Love Medicine", is narrated by Lipsha, a young man with healing powers. His adoptive grandmother Marie asks him to use love medicine to make Nector stop seeing Lulu and be faithful to her instead. Yet Nector chokes to death after eating a turkey's heart, which was meant to be part of the love medicine.
"Resurrection" details Gordie's final descent into death in his grief over June. He reminisces about the early days together after their marriage, and arrives at his mother's house looking for alcohol. When she will not give him any, he drinks Lysol and dies of poisoning.
"The Good Tears" tells the story of the many men Lulu has loved and the many children she has mothered. When Nector burns Lulu's house down, Lyman is inside and Lulu rushes to save him. All of her hair is burned off and her home is destroyed. Years later, in a retirement home, she and Nector reignite their affair. He dies when she is having eye surgery and, after years of mutual antagonism, she and Marie finally bond when Marie becomes Lulu's caretaker.
In "The Tomahawk Factory" and "Lyman's Luck", Lyman supervises the opening of a factory that will produce Indian "artifacts." He is unable to make the factory productive and a final revolt by his workers, who include Lipsha, Marie, and Lulu, finally shuts the operation down. He then makes plans to open a casino.
"Crossing the Water" focuses on Lipsha's quest to find his father. He has only recently learned that his parents were June and Gerry, and he goes to the Twin Cities after a premonition that Gerry will break out of jail. While Lipsha is staying with King and Lynette, Gerry arrives and is nearly arrested again, but quickly escapes when police arrive. As he is driving off, Lipsha discovers Gerry in his trunk and drives him to the Canadian border. They acknowledge each other as family and Lipsha returns home with peace in his heart over his parentage.