Act I:
The citizens of Oz celebrate the death of the Wicked Witch of the West. Glinda descends in her bubble to confirm the circumstances of the Witch's melting ("No One Mourns the Wicked").

The scene then shifts to the birth, years earlier, of the green-skinned Elphaba Thropp. Elphaba suffers an unhappy childhood, facing discrimination because of her skin color and only being raised by her father. At Shiz University, Galinda first encounters Elphaba ("Dear Old Shiz"). In a moment of anger, as she is told that she will be rooming with the spoiled and popular Galinda, Elphaba accidentally reveals an innate magical talent. This impresses Madame Morrible, the headmistress of Shiz, who notes that Elphaba's talents may be of use to the Wizard of Oz. ("The Wizard and I") Galinda is horrified, and takes an immediate dislike to Elphaba. Elphaba also dislikes Galinda, and they each lament that they have no choice but to room together ("What Is This Feeling?").

Doctor Dillamond, a Goat and Shiz University's only Animal professor, is teaching history class when it is interrupted by an anti-Animal slogan on the back of his blackboard, apparently written in blood: "Animals should be seen not heard." After dismissing the class, he confides in Elphaba that something is causing the Animals of Oz to lose their powers of speech ("Something Bad"). Fiyero, a prince, arrives at Shiz and immediately impresses his own brand of cavalier, carefree living on the students ("Dancing Through Life").

Fiyero organizes a party at a local ballroom. Galinda, while preparing for the dance, discovers a black pointed hat in a box and gives it to Elphaba as a 'present'. Galinda convinces a munchkin student named Boq to take Nessarose (Elphaba's wheelchair-bound sister) to the party, more to avoid unwanted attention from Boq than out of a desire to be kind. Nessarose has a crush on Boq and is so overjoyed to be invited that she asks Elphaba if there is any way to repay what she perceives as Galinda's kindness. At the dance, Galinda is surprised by the appearance of Madame Morrible, who gives her a training wand and tells her that Elphaba has insisted she be included in the sorcery seminar. Clearly, despite apparent misgivings, Elphaba has done as her sister requested and found something nice to do for Galinda. Elphaba arrives wearing the hat Galinda had given her, only to be ridiculed. Defiant, she proceeds to dance alone and without musical accompaniment. Fiyero is impressed that Elphaba does not seem to care what anyone thinks of her, but Galinda realizes that this is not true. Feeling guilty, she joins Elphaba on the dance floor, marking the start of a new friendship between the two. After the dance, Galinda and Elphaba talk in their room. Elphaba confides that her father hates her because of her green skin and had forced her mother to eat milk flowers to ensure that Nessarose was not born the same, causing Nessarose to be born early, crippling her and killing their mother. Galinda comforts Elphaba, and, moved by a desire to help her new friend, Galinda decides to give Elphaba a makeover and to make her popular ("Popular").

The next day, Ozian officials take Doctor Dillamond away. The new history teacher arrives with a frightened lion cub in a cage, revealing that Animals that are kept in cages will never learn to speak. Outraged, Elphaba casts a spell over the whole class except for Fiyero, and together they steal the cub and set it free. There is a hint of chemistry between the pair, but Fiyero leaves, embarrassed. It begins raining, and Elphaba takes refuge under a bridge and regrets that it would be impossible for someone like Fiyero to love someone like her ("I'm Not That Girl"). Madame Morrible finds Elphaba and announces that she has been granted an audience with the Wizard. At the train station, Galinda and Fiyero see Elphaba off to the Emerald City. Galinda complains to Elphaba privately that Fiyero's affections toward her seem to be waning. Fiyero has brought flowers for Elphaba as a going away present, and seems to be more interested in her than he is in Galinda. In an attempt to impress Fiyero, Galinda announces that she will change her name to "Glinda" in honor of Doctor Dillamond's persistent mispronunciation of her name. Fiyero does not appear to notice and, feeling bad for Glinda, Elphaba invites her along to see the Wizard.

After a day of sightseeing in the Emerald City ("One Short Day"), Elphaba and Glinda meet the Wizard. Eschewing special effects, which he employs for the benefit of most visitors, he invites Elphaba to join him ("Sentimental Man"). As a test, he asks that Elphaba give his monkey servant, Chistery, the ability to fly using the Grimmerie, an ancient book of spells. Elphaba demonstrates an innate understanding of the lost language and successfully gives Chistery wings. The Wizard reveals an entire cage full of monkeys who now also have wings because of Elphaba's spell, and remarks that they will make good spies to report any subversive Animal activity. Realizing that she has been used and that the Wizard has no power of his own, Elphaba runs away with the Grimmerie, pursued by the palace guards.

Elphaba and Glinda run into the tallest tower, where they hear Madame Morrible declaring to all of Oz that Elphaba is a "Wicked Witch" and is not to be trusted. Falling to the floor, Elphaba enchants a broomstick to fly and tries to convince Glinda to join her in her cause, but Glinda cannot resist the call of popularity and refuses. Leaving Glinda behind, Elphaba promises to fight the Wizard with all her power. When the guards find them in the tower, not seeing Elphaba yet, they run after Glinda. When Elphaba announces it is her that they want, she rises from the stage (knocking over the guards in the process). All of the Ozians see Elphaba levitating and are finally convinced that she is, in fact, a wicked witch. ("Defying Gravity").

Act II:
Time passes, and Elphaba's exploits have earned her the title "The Wicked Witch of the West" ("No One Mourns the Wicked (Reprise)"). Glinda and Morrible hold a press conference to announce Glinda's surprise engagement to Fiyero ("Thank Goodness"). Meanwhile, Elphaba arrives at the governor's residence in Munchkinland seeking refuge. Nessarose, now the governor following their father's death, criticizes Elphaba for not using magic to help her to overcome her disability. To assuage her feelings of guilt, Elphaba enchants Nessarose's jeweled shoes, enabling her to walk. Boq, who is now Nessarose's servant, is summoned and reveals that his affection for Nessarose was put on and that his heart lies with Glinda. Furious, Nessarose miscasts a spell from the Grimmerie, causing Boq's heart to shrink. While Elphaba attempts to save him, Nessarose reflects on how her obsession with Boq has led her to oppress the Munchkin people ("The Wicked Witch of the East"). Elphaba saves Boq by turning him into the Tin Man horrified, Nessarose lays the blame on Elphaba, which because of all the Wizard and Madame Morrible's propaganda, Boq believes without question.

Elphaba returns to the Wizard's palace to free the rest of the winged monkeys. The Wizard attempts to regain her favor by agreeing to set them free ("Wonderful"). Upon discovering a now-speechless Doctor Dillamond among the monkeys, Elphaba rejects his offer and attempts to escape, running into Fiyero in the process. Confirming his true love for Elphaba, he runs off with her. Glinda sees this and is crestfallen that she has been betrayed by those closest to her ("I'm Not That Girl (Reprise)"). In an attempt to finally capture Elphaba, Madame Morrible decides to create a cyclone that will endanger Nessarose.

In a dark forest, Fiyero and Elphaba express their mutual love ("As Long As You're Mine") but are interrupted when Elphaba senses that her sister is in danger. She flies off to help but is too late, arriving just after Dorothy's house has landed on Nessarose, killing her. The palace guards capture Elphaba, but Fiyero intervenes and allows Elphaba to escape before surrendering himself. The guards take him to a nearby cornfield to be tortured until he tells them where Elphaba has fled. At one of Fiyero's family's castles, Elphaba tries to cast a spell to save Fiyero's life but, thinking she has failed, she begins to accept her reputation as "wicked" ("No Good Deed").

Meanwhile, Boq and the citizens of Oz prepare a witch hunt ("March of the Witch Hunters"). Boq claims that Elphaba turned him into the Tin Man as an act of evil, as he does not know that she saved him. The lion cub that Elphaba freed at Shiz is also at the gathering and turns out to be the Cowardly Lion. Boq tells the citizens that because Elphaba fought the lion's fights for him, he never learned to stand up for himself and so the lion has no courage; again, Elphaba's good deed is lost amongst the crowd. Seeing the witch hunt and realizing Nessa's death was no accident, Glinda travels to Kiamo Ko, Fiyero's castle, to persuade Elphaba to let Dorothy go, but she refuses. She does, however, start to talk peacefully with Glinda and starts treating her like a friend again. Elphaba makes Glinda promise not to clear her name and to take charge in Oz. She agrees, and the two confirm a true friendship ("For Good"). As the mob arrives at the castle, Elphaba tells Glinda to hide herself and declares that it is time. She faces the mob and Dorothy throws a bucket of water on Elphaba, apparently melting her. It is revealed that the Wizard is actually Elphaba's father. Glinda tells the Wizard to leave Oz in his balloon, and sends Morrible to prison, before preparing to address the citizens of Oz, returning to the opening scene of the show.

Meanwhile, Fiyero, whom Elphaba had turned into the Scarecrow with her spell to prevent his suffering from the torture, opens a trap door in the castle. Elphaba, very much alive, emerges, and the two are reunited. However, Fiyero tells Elphaba that if the two of them want to be safe, they must leave Oz forever. Elphaba agrees, but first, she says that she wants Glinda to know that she is alive. However, Fiyero insists that nobody can ever know. Glinda addresses the citizens of Oz, proclaiming that she would like to be "Glinda the Good" as she will reform the government. Elphaba and Fiyero leave Oz forever, as Glinda celebrates with the citizens of Oz ("Finale").

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