The following version of this book was used to create the guide: Henderson, Eleanor. Twelve-Mile Straight. Ecco (HarperCollins), 2017.

The novel begins with the lynching of Genus Jackson, on a summer night in 1930, in Cotton County, Georgia. The reason for the lynching is the birth of twins to Elma Jesup, one black, and one white. Her father, a sharecropper named Juke Jesup, and her fiancé, the grandson of the landlord, Freddie Wilson, insist that Genus is the father of the black baby, and that he raped Elma. However, the narrator quickly reveals that Elma was not raped by Genus. In fact, her father was raping Nan, the black daughter of Ketty, their recently deceased house servant. The black baby, Wilson, is Nan's.

As the story continues, the third-person narrator offers new perspectives on both the events in the year following the lynching, and the events leading up to it. Through flashbacks, the reader learns that Elma's mother died in childbirth, and she was raised primarily by Ketty. Elma considered Ketty like a mother, and Nan like a sister. She and Nan had an especially close bond because Nan could not talk. Ketty cut out Nan's tongue with a scalpel when she was a baby, ostensibly so Nan would not succumb to tongue cancer, a disease that runs in their family, and eventually killed Ketty. Elma taught Nan to read and write, and the two can communicate almost wordlessly — yet Elma didn't know about her father's treatment of Nan. Elma was attracted to Genus, but it was Nan who had a romantic relationship with him.

After the lynching, Freddie flees town. Juke denies having anything to do with Genus's murder, and instructs Nan and Elma to pretend that both the babies are Elma's. They do so successfully until they travel together to Atlanta with the county doctor, whose son, Oliver Rawls, is a hematologist interested in studying the babies' blood. There, Nan's breasts leak, and she nurses Wilson, revealing herself as his mother. Oliver Rawls agrees to keep their secret, and proposes marriage to Elma.

Around the same time, Nan's father, Sterling, returns to Cotton County as part of a chain gang. Nan and Elma believed that he had fled for Baltimore when they were little girls to find a better job. Freddie is also on the chain gang, having been apprehended for stealing from a chicken coop after fleeing town for the lynching. Sterling's flashbacks reveal that Ketty and Juke had a sexual relationship, and that Ketty suffered from mental illness. He believes that she cut out Nan's tongue not to keep her safe from cancer, but to keep her silent.

Sterling and Freddie reveal themselves to Elma on the day of her wedding to Oliver. Freddie is then arrested in connection to Genus's murder, as is Juke. At the hearing, Juke admits that he assisted in the lynching, and that baby Wilson is his son. Juke is charged with murder, while Freddie is not. Freddie's grandfather, George, the most powerful man posts Juke's bail, as well as Sterling's bail. Juke was best friends with George's son, and George mentored Juke, as well as funded the illegal gin still that Juke ran on the farm. They had a falling out, though, about Elma's pregnancy, and Freddie's lack of commitment, and so George's generosity surprises everyone. In fact, George wants to hire Sterling to kill Juke. George's wife, Parthenia, suspects the plot, and warns Elma to go home and protect her father.

Shortly after the trial, Oliver loses his father's house to foreclosure, and is appointed to the board of Warm Springs, a polio rehabilitation center and spa facility frequented by Franklin Roosevelt. Oliver, Nan and Wilson temporarily relocate to Warm Springs. While they are there, Oliver discovers that Wilson has sickle cell anemia, a genetic disease that also afflicted Genus. He realizes that Wilson is not Juke's son after all, but his grandson. Nan is the daughter of Ketty and Juke, and Wilson is Genus's son.

Meanwhile, at the farm, Juke kills Freddie after catching him raping Elma. George instructs Sterling to shoot Juke on the spot, but Sterling refuses, and George shoots Juke instead, paralyzing him.

The epilogue takes place six years later. Elma, Oliver, and Elma's daughter Winna live on the farm with Nan, Nan's husband Frank, Wilson, and Sterling. Nan is expecting a baby. Elma and Oliver are planning to move six miles down the road so they can take care of Juke, who cannot walk or talk. Wilson and Winna hold a May Day party, using the pole that Genus was killed on as a Maypole.