Once upon a time in the far-off land of Oz, a green girl named Elphaba Thropp is born to a Unionist minister named Frex and his Desperate Housewives-esque wife Melena in Munchkinland. Not your typical fairy tale fare here.
Elphaba spends her early years with her alcoholic mother, her mother's lover (Turtle Heart), her mother's old nurse (Nanny), and her devout father. Her childhood is a rough one, since her green skin makes her a social outcast, and her own family is alternately repulsed by her and scared of her. During this time the Wizard also arrives and takes over Oz. He's a cruel dictator and starts oppressing various ethnic groups and Animals. Melena eventually becomes pregnant again, likely with Turtle Heart's child. She has another girl, named Nessarose, who lacks arms. Melena later dies while giving birth to her third child, a boy named Shell.
Next, we jump forward to Elphaba's wild and crazy college years. She attends Shiz University, where she is plagued by the manipulative and dangerous headmistress, Madame Morrible. Nessarose comes to Shiz a few years later, accompanied by Nanny. Elphaba and Nessa spent the bulk of their childhood in the Quadling Country, following their father Frex on his missionary work there. Like Frex, Nessarose is extremely religious, and Elphaba resents the favoritism her father shows towards Nessa. She especially resents the special shoes that Frex made for Nessarose.
While at Shiz, Elphaba also befriends Galinda, a spoiled girl who eventually changes her name to Glinda; Boq, a Munchkinlander who knew Elphaba as a child; Crope and Tibbett, two of Boq's co-workers at his summer library job; Fiyero, a prince from the Vinkus; and Avaric, a conceited rich boy who acts more as a frenemy to Elphaba than anything. Elphaba becomes involved with the crusade of Doctor Dillamond, a Goat who is studying the origins of the Animals in an effort to stop the Wizard's anti-Animal legislation.
Doctor Dillamond is murdered, and Elphaba and Glinda eventually discover that Madame Morrible's servant, Grommetik, committed the crime. Madame Morrible then tries to recruit Elphaba, Glinda, and Nessarose to work for the Wizard as spies. Elphaba and Glinda run off to the Emerald City to see the Wizard themselves, and Elphaba tries to convince him to stop oppressing the Animals and other people in Oz. When the Wizard refuses to listen to her, Elphaba decides to stay in the Emerald City and join an underground rebellion.
A few years later, Elphaba is a member of the underground. She meets Fiyero again and the two begin an affair. Elphaba eventually tries and fails to assassinate Madame Morrible, and Fiyero is killed by the secret police. A devastated Elphaba joins a convent. Years later, she and her presumed son, Liir, journey to Fiyero's home in the Vinkus. Elphaba hopes to apologize to Fiyero's wife, Sarima, but Sarima refuses to let her. Elphaba, Liir, and later Nanny spend many years living with Sarima and her family until the Wizard's forces arrest and kill Sarima and her family, except for her youngest daughter, Nor, who becomes a political prisoner.
Having assumed the guise of a Witch after leaving the convent, Elphaba now begins to practice magic. Nessarose, who had been the ruler of Munchkinland and a Witch in her own right, is killed when Dorothy's house drops from the sky during a tornado. Elphaba returns for the funeral and has a short-lived reunion with Glinda, also a Witch. The two argue over politics and Nessa's shoes, which Glinda has given to a girl named Dorothy. They part on frosty terms.
Elphaba has a meeting with the Wizard and learns he's from another world. She then learns that it's likely the Wizard is her biological father. Elphaba starts to lose her grip on reality and grows obsessed with Dorothy and Nessa's shoes. Finally the Wizard sends Dorothy and her traveling companions to Elphaba's house to kill her. After a tense confrontation, Dorothy accidentally kills Elphaba by tossing water on her. Elphaba dies and is remembered across Oz as the cruel Wicked Witch of the West.