Narrated by the novel's protagonist, Billie Jo Kelby, Out of the Dust opens with Billie Jo explaining that her mother gave birth to her in August 1920 on the kitchen floor of their farmhouse in Cimarron County, Oklahoma. Billie Jo has a boy's name because her father wanted a son. In 1934, Billie Jo is thirteen. She is a fierce piano player who likes apples and who can handle any farm work her father tells her to do. Her mother is pregnant with the couple's second child.
At school, there is a farewell party for Billie Jo's friend Livie Killian, who is moving with her family to California in search of work. The family is among the many Dust Bowl residents who flee Oklahoma, Texas, and Kansas, driven from their homes by unemployment and drought. Billie Jo is asked by the music teacher, Arley Wanderdale, to play at the Palace Theatre. Billie Jo is careful when asking her mother for permission because she knows her mother doesn't approve of her prioritizing piano playing, even though Ma—herself a classically trained pianist—is the one who taught Billie Jo how to play. The performance goes so well that Arley asks her to play at the President's Birthday Ball fundraiser.
Billie Jo comments that the family's wheat crop has been lousy for three years; she and her parents are thin from lack of food. Demand for wheat during WWI has led to overproduction on local farms, precipitating the loss of moisture-retaining grasses and the development of a phenomenon that sees loose soil blown everywhere by strong winds. In the Dust Bowl, soil erosion has meant that there is dust throughout people's homes, getting on their plates, in their food, and thickening their milk. As part of the Roosevelt government's New Deal legislation, Billie Jo's father Bayard has the opportunity to take out a loan to plant a new wheat crop. Ma doesn't think it's a good idea to continue planting wheat when they have no hope of rain, leading the couple to argue.
Dust storms blow through the county, destroying the surviving plants on the family's farm and filling the schoolhouse with dust during the "six-weeks test." Billie Jo scores highest in her grade. Ma wants Bayard to put in a pond to collect water for the crops; he believes water will seep away faster than he can pump it from the well. In the summer, Billie Jo enjoys accompanying Arley and his band to play gigs around the county. She earns a few dimes, which Ma saves for her in a secret hiding place. A small amount of rain falls; Billie Jo watches her mother stand naked in the rain.
The air of optimism dissipates when Bayard leaves a pail of kerosene (lamp fuel) next to the kitchen stove. Mistaking it for water, Ma starts a fire when she pours the kerosene. She rushes outside, leaving the pail in the kitchen. To save the house, Billie Jo grabs the pail and tosses it out the door; however, her mother has turned back to the house, so the kerosene lights her apron on fire. Billie Jo suffers severe burns to her hands as she puts out the flames on her mother's body. When the doctor attends to her, Billie Jo can't feel the pain of her hands even as he cuts away the damaged skin.
Following the accident, Ma writhes in pain while covered in bandages. Bayard carefully gives her water and sees to her, but eventually he finds some of the money Ma has been hiding and goes on a drinking binge in Guymon. Billie Jo struggles to give her mother water with her own bandaged hands. Ma gives birth in August, dying as she does. The baby boy dies within days of Ma, and the two are buried together. Billie Jo names her brother Franklin, after the president. While grieving, Billie Jo resents that locals tacitly blame her for the deaths; she sees Daddy as responsible because he left the kerosene by the stove and disappeared on a bender when his wife needed him.
In October, Bayard takes a job digging holes for electrical towers. Billie Jo can't be in the same room as her mother's dusty piano. She doesn't try playing piano again until the December dance revue. She appreciates that Mad Dog Craddock, a rival youth performer, doesn't treat her differently because of her deformed hands. Bayard accompanies Billie Jo to the President's Ball this year; an air of hope leads them both to feel temporary relief from their woes. A family of five moves into the schoolhouse while they search for a livelihood. The school community welcomes them with donations and food.
Billie Jo practices piano for a competition in which she places third, earning a dollar. She believes the judges took pity on her because she still can't play properly. Bayard suggests that he should take night-school classes as a fallback in case the farm fails. Billie Jo suspects he wants to meet women. More dust storms kick up. During one, Billie Jo struggles to find her way home with no visibility. Once back, she realizes her father has gone out in search of her; he returns hours later, bloody from having bumped into things. A local man and his wife both die of dust pneumonia. Billie Jo imagines the wife actually died of heartbreak.
Billie Jo is honest about the fact that she is heartsick over Mad Dog, someone she has treated as a nemesis. She would like him to court her, but when they walk together he is mostly silent, like her father. Mad Dog leaves town for a job at a radio station in Amarillo, but he returns weekly to visit his family farm. He makes a habit of stopping in to see Billie Jo. Meanwhile, potentially cancerous spots appear on Billie Jo's father's face. She is frustrated that he isn't seeing a doctor about it; his own father died of the same ailment. Bayard spends a lot of time digging a giant pond in the yard. She wonders if he is digging his own grave and merely calling it a pond.
In August, Billie Jo leaves home in the middle of the night. Taking only a few biscuits, she hops on a boxcar heading west. She travels for two days through desolate landscapes before meeting a man who travels with her. He is guilt-ridden for having abandoned his wife and children. She gives him her day's ration of biscuits. When she wakes up, he has stolen the rest of her food and left the photo of his family. In Arizona, Billie Jo gets off the train and is given water and food by a government agent. She sends word back to her family that she is coming home, then gets on another train and returns. Once back, she calls Bayard "Daddy" again and speaks of a desire to make the most of her life on the farm. He promises to talk to the doctor when she admits to her worry about losing him. She feels herself forgiving him for the kerosene and herself for her part in the tragedy.
Doc Rice cuts the growths off Bayard's face and reprimands him for not having come sooner for medical attention. The doctor also assesses Billie Jo's hands and tells her that they will heal fine if she uses them. Billie Jo learns that her father used to dream of running away from his life as a wheat farmer. She realizes they have more in common than she thought.
Billie Jo reveals that, while she was away, her father was kept company by Louise, the night school teacher he has been courting. Louise comes to the farm for dinner increasingly often; Billie Jo steadily learns to trust her and appreciate her way of not imposing herself on Ma's place in their memories. She is also grateful that her father acts politely when Louise is around, tidying the kitchen as best he can after dinner. Louise is also adept at keeping the peace between Billie Jo and her father, who are both fiery redheads.
The novel ends with Billie Jo commenting that she practices piano for half an hour every morning before school; it helps the skin and scars stretch out on her hands. Billie Jo concludes that the hard times she and her father have been living through aren't just about poverty and dust; they're about losing one's spirit. She is determined to stay and grow in one place, like her father has. She hopes that Louise will move in with the family, as she can see that Louise is helping brighten the lives of both her and her father.
