Set in Italy in year 1628, during the Spanish occupation, it was the first example of historical novel in Italian literature. Although the setting had been chosen by Manzoni with the actual intent to refer to the Austro-Hungarian domination over Northern Italy, the novel became known also because of its good descriptions of some historical events of the 17th Century, mostly the ones referring to the plague that struck Milan between 1629 and 1631.
- Lorenzo Tramaglino, or in short form Renzo, is a young silk-weaver of humble origins, engaged to Lucia, whom he loves deeply. Initially rather naive, he becomes more cunning throughout the novel as he is confronted with many difficulties: he is separated from Lucia and then unjustly accused of being a criminal. Renzo is somewhat short-tempered, but also gentle and honest.
- Lucia Mondella is a pious and kind young woman who loves Renzo. She is forced to flee from her town to escape from Don Rodrigo in one of the most famous scenes of Italian literature, the Addio ai Monti or "Farewell to the mountains."
- Don Abbondio is the priest who refuses to marry Renzo and Lucia because he has been threatened by Don Rodrigo's men; he meets the two protagonists several times during the novel. The cowardly, morally mediocre Don Abbondio provides most of the book's comic relief; however, he is not merely a stock character, as his moral failings are portrayed by Manzoni with a mixture of irony, sadness and pity, as has been noted by Luigi Pirandello in his essay "On Humour" (Saggio sull'Umorismo).
- Fra Cristoforo is a brave and generous friar who helps Renzo and Lucia, acting as a sort of "father figure" to both and as the moral compass of the novel. Fra Cristoforo was the son of a wealthy family, and joined the Capuchin Order after killing a man. He dies because he has contracted the plague while trying to help the sick.
- Don Rodrigo is a cruel and despicable nobleman and the novel's main villain. He decides to prevent with the force Renzo and Lucia's marriage, threatens to kill Don Abbondio if he marries the two and tries to kidnap Lucia. He dies in the plague, after repenting for his sins.
- L'Innominato (literally: the Unnamed) is probably the novel's most complex character, a powerful and feared criminal who is torn between his ferocious past and the increasing disgust he feels for his life. Based on the historical character of Francesco Bernardino Visconti, who was really converted by a visit of Federico Borromeo.
- Agnese (Agnes) is Lucia's wise mother.
- Federico Borromeo is a virtuous and zealous cardinal. Historical character.
- Perpetua is Don Abbondio's loquacious servant.
- La Monaca di Monza (the Nun of Monza), whose real name is Gertrude (Gertrude) is a tragic figure, a bitter, frustrated and ambiguous woman. She befriends Lucia and becomes genuinely fond of her, but her dark past still haunts her. Based on a real historical character.
- Griso is one of Don Rodrigo's henchmen, a silent and traitorous man. He dies in the plague, contracting the illness from his master whom he tried to rob.
- Dr Azzecca-garbugli ("Quibble-weaver") is a corrupt lawyer, friend to Don Rodrigo.
- Count Attilio is Don Rodrigo's malevolent cousin.
- Nibbio (Kite - the bird) is the Innominato's right-hand man.
- Don Ferrante is a phony intellectual and erudite scholar who believes the plague is caused by astrological forces.
- Donna Prassede is Don Ferrante's wife, who is willing to help Lucia but is also a slightly arrogant bigot.