Creech wrote Walk Two Moons in the first person, revealing the thoughts and feelings of the protagonist, Salamanca Tree Hiddle (Sal), a young girl searching for her mother. The novel is a story-within-a-story. Creech writes about Sal's road trip to Idaho with her eccentric grandparents, and during the trip, Sal tells her grandparents about her friend Phoebe Winterbottom and the disappearance of Phoebe's mother. In the telling of her story, the tragic events of her own mother's disappearance and parallels between the situations and reactions of the girls are revealed.
Sal lived on a farm in Bybanks, Kentucky, with her mother and father. Her parents seemed to love each other very much and Sal, "a country girl at heart," was at home on the farm. Sal's mother has a stillborn baby and, afterward, becomes quite depressed. She can't seem to work through her grief. Her solution is to go away "to clear her head, and to clear her heart of all the bad things." Sal and her father try to persuade her not to go, but she leaves anyway. Sal and her father are lost without her mother, but eventually they settle into a routine of their own. Sal is angry at her mother for leaving. Her mother sends her postcards from every stop the bus makes en route to Idaho. One day, Sal's father learns that her mother won't be coming home. Sal's mother is killed in a bus accident. Her father goes to Idaho to bury Sal's mother.
Not long after Sal's father returns from Idaho, he decides to sell the farm. He can't stay there because memories of Sal's mother are everywhere. Sal can't bear the thought of selling the farm. She cannot let go of the memories of her mother and, because she has no closure on her mother's death, such as a funeral, she continues to hope that one day her mother will come home. Sal is angry and she is in denial about her mother's death. Her father rents the farm instead of selling it, and the two of them move to Euclid, Ohio where Margaret Cadaver, a new friend of her father's, lives. They rent a small house a few blocks from Margaret's. Sal's father met Margaret when he went to Idaho. Margaret, the only survivor of the crash, had been sitting next to Sal's mother on the bus.
Sal hates the new house and she doesn't want to have anything to do with Margaret. She is sad and angry, and she misses her mother terribly. She also feels guilty. She feels it is her fault her mother left in the first place. Sal meets Phoebe Winterbottom, who lives across the street from Margaret. Phoebe is in Sal's class at school and the two girls become friends. They spend time at each other's house and both of them visit Mary Lou Finney from time to time. Mary Lou has a cousin named Ben who is living with her family. He is also in Sal's class, and Sal and Ben become more than friends — they fall in love.
Sal begins to realize that Phoebe's mother seems unhappy. She is not surprised when Phoebe goes home from school one day and finds that her mother has disappeared. Mrs. Winterbottom has left Phoebe, her sister, and Mr. Winterbottom notes and has stocked the freezer with food. Phoebe is angry and hurt because her mother has abandoned her. Phoebe acts like an "ornery donkey." Sal realizes this is the way she must have acted when her mother left her. Eventually, Phoebe's mother does return to the house with a young man who, she tells the family, is a son she had put up for adoption before she married Mr. Winterbottom. Creech leads readers to believe that Mrs. Winterbottom will be staying home and that major changes will take place in the Winterbottom household.
At the same time Mrs. Winterbottom leaves, anonymous messages are left on the Winterbottom's front porch. Phoebe is convinced a "lunatic" has left the messages. Sal and Phoebe spend time investigating the disappearance of Phoebe's mother and the mystery messages. Phoebe believes the "lunatic" is a young man who came to the door one day — the young man turns out to be her half brother, and the "lunatic" who was leaving the messages, turns out to be Mrs. Partridge, Margaret's blind mother.
After everything is more or less settled with Phoebe's family, Sal's grandparents, Gram and Gramps Hiddle, suggest they take a road trip from Ohio to Idaho to see Sal's mother's grave. They take the same route that Sal's mother took when she left home on the bus. Throughout the trip, Sal tells her grandparents about Phoebe, the disappearance of Phoebe's mother, the "lunatic," and Sal's budding romance with Ben.
Sal and her grandparents travel through Indiana, Illinois, Wisconsin, Minnesota, South Dakota, Wyoming, and finally Idaho. In Illinois they stop and put their feet in Lake Michigan. Sal understands that when Gram says, "Huzza, huzza!" she is expressing joy. Her grandmother dances with Indians in Wisconsin and gets bitten by a poisonous snake in South Dakota, forcing her to spend the night in the hospital. They see Mount Rushmore and Old Faithful. By the time they get to Coeur D'Alene, Idaho, Gram is not feeling well. They drive directly to the hospital and Gram is admitted. The doctors tell Sal and Gramps that Gram has had a stroke; Gram dies early the next morning. Sal is not at the hospital when Gram dies, because she drove Gramps' car to Lewiston to see the site of her mother's accident. She then spends time in the cemetery at her mother's grave, in an attempt to memorize every detail. Sal is able to put closure on her mother's abandonment of her and can accept her mother's death. She realizes that the trip to Idaho "had been a gift from Gram and Gramps to [her]. They were giving [her] a chance to walk in [her] mother's moccasins — to see what she had seen and feel what she might have felt on her last trip."
Sal and her father return to the farm in Bybanks, Kentucky to live. Gramps is living with them and Gram is buried in the Aspen grove. Gramps has a new beagle puppy named Huzza Huzza. Sal misses her mother, but she is happy being back on the farm she loves so much.