José Rizal's Noli Me Tangere (1887) opens with a dinner party hosted by Captain Tiago in San Diego, Philippines, during the 1880s under Spanish colonial rule. Among the guests are influential Spanish friars, including the corrupt and vindictive Father Dámaso and the calculating Father Salví. Don Crisóstomo Ibarra arrives after seven years studying in Europe, expecting to reunite with his father, the respected landowner Don Raphael. Instead, he learns devastating news: his father was falsely imprisoned on charges orchestrated by Father Dámaso and others who envied his wealth and influence. Don Raphael died in prison, and Father Dámaso denied him Christian burial, leaving his body cast into the sea—a profound spiritual violation in Catholic Filipino culture.

Despite this tragedy, Crisóstomo reconnects with his childhood love, María Clara, Captain Tiago's beautiful daughter. The two quickly reaffirm their deep affection and engagement. Crisóstomo, inspired by European enlightenment ideals, decides to honor his father's memory by building a school in San Diego to provide Filipino children with proper education. He consults with Don Anastasio (Tasio), a philosopher considered mad by society for his critiques of the church, who enthusiastically supports the project while warning Crisóstomo about powerful enemies.

The novel introduces the tragic story of Sisa, a desperately poor but devout woman whose two young sons, Crispín and Basilio, work as sextons in the church. When young Crispín is falsely accused of stealing two pesos, he suffers brutal beatings. The boys are prevented from visiting their mother, and Crispín apparently dies from the abuse while Basilio escapes. Sisa searches frantically for her sons, but after being arrested and abused by soldiers, the trauma drives her mad. She wanders San Diego in a daze, her mind shattered by loss and injustice.

During a festive boat outing with María Clara and friends, Crisóstomo meets a mysterious boatman named Elías. When a crocodile attacks, both men work together to kill it, forging a bond. Elías, it's revealed, is wanted for allegedly assaulting Father Dámaso. He becomes Crisóstomo's unlikely ally, though their philosophies differ sharply.

At a town festival, the ceremonial laying of the school's cornerstone nearly ends in disaster when the supporting crane collapses. Elías saves Crisóstomo from being crushed, then warns him the "accident" was actually an assassination attempt. Crisóstomo, shocked, cannot believe he has enemies. At a subsequent dinner, Father Dámaso deliberately provokes Crisóstomo with escalating insults about his family until Crisóstomo attacks him with a knife. Only María Clara's intervention prevents murder. The church immediately excommunicates Crisóstomo, effectively destroying his social standing and canceling the school project.

The excommunication separates Crisóstomo from María Clara, who falls gravely ill from the trauma. Captain Tiago, fearful of clerical disapproval, cancels their engagement and introduces Alfonso Linares, a Spaniard, as her new suitor. However, the Captain General—the highest secular Spanish authority—arrives and takes interest in the case. Charmed by María Clara and recognizing clerical overreach, he forces the church to begin reconciling with Crisóstomo.

Meanwhile, Elías reveals himself as connected to revolutionary elements seeking Philippine independence. He tries to recruit Crisóstomo to lead the movement, recounting his own family's multi-generational suffering under Spanish rule. Crisóstomo, believing in gradual reform within the system, refuses to support violent revolution. Their philosophical debate—reform versus revolution—forms the novel's ideological heart.

A revolutionary attack on San Diego occurs, orchestrated by rebels with whom Crisóstomo has no connection. However, Father Salví and the authorities immediately blame him. Elías rushes to warn Crisóstomo to burn incriminating papers. While doing so, Elías discovers that Crisóstomo's great-grandfather was the wealthy landowner who destroyed his family generations ago. Devastated by this revelation, Elías nevertheless returns to protect Crisóstomo by destroying evidence before soldiers arrive.

The revolutionaries are captured, tortured, and executed in show trials. Crisóstomo is imprisoned and requests to be hanged in solidarity with them. Tasio dies trying to reach Crisóstomo's house, presumably to help him. María Clara and Captain Tiago flee to Manila, where Tiago arranges her rushed marriage to Linares.

In Manila's darkness, María Clara encounters Crisóstomo by the water—Elías has freed him. She confesses her deepest secret: Father Dámaso is her biological father, the product of his violation of her mother. She agrees to marry Linares to protect Crisóstomo, using her influence to help him escape. Crisóstomo and Elías attempt to flee across a lake but are shot at by Civil Guard soldiers. Both survive, though authorities believe them dead.

Hearing of Crisóstomo's supposed death, María Clara refuses marriage and begs to enter a convent. Father Dámaso reluctantly agrees, fearing for her safety under Father Salví's control but considering it better than her death. Meanwhile, Basilio finds his mother Sisa wandering mad through the streets. She briefly recognizes him before dying in his arms.

The novel's bleak epilogue reveals the survivors' fates: Captain Tiago descends into opium addiction and gambling. María Clara, trapped in the convent, suffers sexual violence from Father Salví and loses her sanity. Crisóstomo and Elías remain fugitives, legally dead. Through these tragic conclusions, Rizal demonstrates that under colonial rule, neither reform nor revolution can succeed, and individual virtue cannot overcome systemic evil.