Many readers will remember the story of the Wicked Witch of the West. In this novel, Maguire explores possible motivations behind such a person. Frex and Melena, humble peasants in Munchkinland, welcome their first born, Elphaba, in the beginning of this novel. Frex, a minister of the religion of Unionist, constantly fears punishment for sin, both known and unknown. Despite the impending birth of his first child, he travels to preach against dangerous entertainment, specifically, the Clock of the Time Dragon. A cousin of Frex wrote to him about a sideshow type experience that sweeps through Oz. The clock, made up of multiple windows filled with puppets, like a complicated cuckoo clock, shows what observers assume to be future events.

Alone in a land were she has no friends Melena goes into labor. Some elderly, local women arrive to aid with the birth. They supply Melena with addictive pinobble leaves to dull the pain. In a stupor, she delivers a healthy baby girl. The women horrifically discover though, that the child's skin appears inexplicably, green.

Frex and Melena struggle with their daughter's odd skin color, keeping her in private much of the time. With the arrival of Melena's childhood nurse, Nanny, however, young Elphaba begins to socialize with children her own age. At the same age the nomadic Turtle Heart, joins the family, enchanting them with his glass blowing abilities. Melena, lonely from Frex's frequent missionary journeys, begins a passionate affair with Turtle Heart. One of Turtle Heart's creations, a looking glass, captures young Elphaba's attention. In the end of the first section, Elphaba wonders off into the countryside; the family finds her in the arms of an unknown kind of beast, gazing into the looking glass.

Time quickly jumps ahead. In the next section, entitled Gillikin, Elphaba starts college in Shiz, a large town in the area of Oz called Gillikin. Her roommate there, Galinda, ignores her much of the first semester. In college, Elphaba becomes dedicated to Animal rights. In this novel, Animals( capitalized, as opposed to animals, lowercase ) live much like humans. They live and work in mainstream society. They talk, and many walk upright. However, the new government of Oz seeks to remove rights from Animals. Already, they suffer many restrictions on travel and employment. Galinda works with a Dr. Dillamond, a professor at Crage Hall who is also a Goat. During her first year, though, Galinda's guardian or personal assistant, Ama Clutch, discovers Dr. Dillamond murdered in his study. Elphaba blames the head of the school, Madame Morrible and her robot-like assistant, Grommetik. After seeing the murdered Dr. Dillamond, Ama Clutch goes mad and lives in the infirmary at the school. Galinda suspects the madness to be a cover-up by Madame Morrible.

After Ama Clutch's death, Elphaba and Galinda, now Glinda, travel to Emerald City and gain a rare audience with the Wizard. Their worries receive no attention, however. Elphaba sends Glinda back to Shiz and disappears into Emerald City.

Some years later, an old friend from Shiz, Fiyero, bumps into Elphaba in Emerald City, the capital of Oz, at a chapel of Saint Galinda. He follows her to her run down apartment and begs for information on her life. Though at first she resists, due to his persistence and Elphaba's loneliness, the two begin an affair. During the course of their ensuing affair, he learns that she plays a minor role in some plots against the Wizard, the current ruler of Oz. Specifically, Elphaba must murder Madame Morrible, who works for the Wizard. When the time comes to carry out her part of the antigovernment plan, she fails. The same night, Fiyero returns to Elphaba's apartment, where Gale Force soldiers ambush and attack him. Everyone presumes Fiyero dead.

After some time of mental and physical recuperation in a Mauntery, which is like a convent, Elphaba travels to Vinkus, Fiyero's homeland, to make amends with Fiyero's widow and children. Sarima, the widow, refuses to discuss anything about Fiyero with Elphaba. She offers Elphaba rest and housing, however. Elphaba takes up residence in a tower of the castle. A young boy, Liir, the son of her and Fiyero, also lives there, having come with her from the Mauntery. Elphaba, however, cannot remember the circumstance of Liir's birth. Therefore he never knows for certain whom his parents are. Only the narrator reveals this information.

After Elphaba lives with Sarima for some months, Nanny tracks Elphaba down. She insists on moving in. She explains that she previously cared for Elphaba's sister, Nessarose, who was born with no arms. Thanks to jeweled slippers, bewitched by Glinda, Nessarose no longer needs Nanny. After Nanny finds, Elphaba, she also receives word that her sister, Nessarose, orchestrated the secession of Munchkinland from Oz, a positive step away from the tyranny of the Wizard. Elphaba travels to see her sister after years of separation, using her newly discovered flying broom, which she received from an old Maunt upon leaving the Mauntery. She refuses to stay and help in Nessarose's political endeavors and returns to Vinkus.

Years later, during the fated tornado of the original story, Dorothy Gale's house falls on Nessarose, now called the Wicked Witch of the East, due to her strict rule of Munchkinland. Elphaba is now called Wicked Witch of the West, or simply the Witch, largely because she refuses to fight the rumors that spread about her. The Witch attends the funeral of her sister. She only becomes interested in Dorothy when she learns that the girl wears Nessarose's jeweled slippers.

Fate brings Dorothy and the Witch together after the Wizard demands that Dorothy must kill the Witch before he will grant Dorothy's wish to return home. Dorothy journeys, with the Cowardly Lion, Nick Chopper, the tin man, and the Scarecrow to Kiamo Ko, to the castle in Vinkus. There Dorothy confesses that she, instead of seeking death for the Witch, wishes to ask forgiveness. Upon the demand of the very thing she never received from Sarima, who is now dead, the Witch becomes distraught. She accidentally catches her clothes on fire chasing Dorothy with her flaming broom. When Dorothy tries to save her with a bucket of water, the Witch dies due to her deadly allergy to water.