The people of Egypt acclaim the exultant Giulio Cesare, who has just defeated his rival Pompeo in battle. When Cornelia and Sesto, wife and son of Pompeo, come to beg Cesare for a cessation of hostilities, the Roman tribune Curio confesses that he has long loved Cornelia. Cesare agrees to receive Pompeo if he comes in peace, but Achilla, general of Tolomeo, King of Egypt, brings the head of Pompeo as a token of friendship, offering hospitality at the same time. Cesare angrily rejects the cruel deed and Cornelia faints. Achilla is struck by her beauty. Recovering from her swoon, Cornelia wishes to kill herself, but is restrained by Curio, who offers to avenge her if she will be his wife. She rejects his offer. She can find no source of comfort, but Sesto resolves to seek vengeance.
Cleopatra, co-ruler of Egypt with her brother Tolomeo, resolves to be sole ruler. Hearing from her confidant Nireno of Tolomeo's overtures to Cesare, she decides to go to Cesare herself, to press her claim to the throne. Tolomeo confronts her, suggesting she return to women's weapons, the needle and spindle, and leave Egypt to him, but she answers him spiritedly and sets off with Nireno. Achilla reports to Tolomeo who is angered at Cesare's rejection. Achilla suggests that Cesare be killed as Pompeo was, and offers to carry out the deed if Tolomeo will grant him Cornelia.
Cesare meditates on the transience of life as funeral rites are celebrated for Pompeo. Cleopatra presents herself, pretending to be Lydia, one of her own attendants. He is bewitched by her beauty and promises her redress against Tolomeo, whom she accuses of having deprived her of her patrimony. She and Nireno watch as Cornelia bids a formal farewell to her dead husband and draws a sword from among his weapons, planning to kill Tolomeo. She is prevented by Sesto, who says it is for him to take revenge. Hoping that Sesto will assist her path to the throne by killing Tolomeo, Cleopatra, without revealing her identity, offers assistance to Sesto, who rejoices in the prospect of revenge. Nireno will guide him. Cleopatra looks forward to power and love.
Tolomeo welcomes Cesare, who replies politely but makes it clear he disapproves of the murder of Pompeo. Neither trusts the other and Cesare likens himself to the hunter stalking his prey. Achilla brings Cornelia and Sesto to Tolomeo. They abuse him and Sesto offers single combat, but he orders them imprisoned, promising to reserve Cornelia for Achilla, while having designs on her himself. Cornelia refuses Achilla's offer of freedom for herself and her son if she will marry him. Sesto is taken to prison, Cornelia sent to work in the harem garden. Mother and son bid one another farewell.
Having fallen in love with Cesare and hoping to arouse a reciprocal passion, Cleopatra stages a pageant (in which she herself takes part, representing Virtue enthroned, surrounded by the muses) for his benefit; he is enchanted.
Cornelia laments. Fleeing from the advances of Achilla, she runs into Tolomeo, who offers love on his own account. Her scornful rejection provokes his rage. Sesto restrains his mother from leaping from the walls to be devoured by the wild beasts outside and swears to avenge their wrongs. Nireno has been ordered to place Cornelia in Tolomeo's harem, but promises to take Sesto as well, so he may kill the king. Both he and his mother look forward to vengeance.
When Cesare is shown to Cleopatra's apartments, she pretends to be asleep to find out if he loves her. He is so enraptured he murmurs that she must become his wife, but, still believing her to be Lydia, he is disconcerted when she accepts. They are interrupted by Curio with the warning that Cesare's camp has been attacked by Tolomeo.
Failing in her entreaties to keep Cesare by her side, Cleopatra reveals her identity and declares that her presence will be enough to quell the attack, but finding that this is not so, urges Cesare to flee. Cesare rushes out into the midst of his enemies, leaving Cleopatra a prey to conflicting emotions. Tolomeo is surrounded by his favorites, Cornelia among them. She reacts indignantly when he gives her the handkerchief signifying she is the chosen one for the night. Sesto bursts in, taking the sword Tolomeo has left lying, but Achilla takes it from him and gives it back to Tolomeo. He reports that Cesare and Curio are dead, but Cleopatra has fled to the Roman camp and is rousing the soldiers. Tolomeo rejects Achilla's request for Cornelia in return for his services and sets off to do battle, leaving Sesto so despairing of the prospect of revenge that he thinks of killing himself, but Cornelia urges him to seek battle with Tolomeo.
Achilla has turned on the ungrateful Tolomeo and gathered a band of soldiers. Defeated and captured by Tolomeo, Cleopatra is still defiant. Tolomeo has her put in chains and threatens to tame her rebellious spirit. She laments her fate.
Cesare had saved himself by jumping into the harbor, but he is now alone, without his army. Achilla, lying mortally wounded on the shore, confesses to Sesto and Nireno that he advised the killing of Pompeo and stirred up the rebellion against Cesare in the hope of winning Cornelia. He gives them a seal which his followers will obey and dies. Cesare steps forward and takes possession of the seal and sets off with Sesto and Nireno to rescue Cleopatra and Cornelia.
Surrounded by her weeping women, Cleopatra fears that Tolomeo is about to kill her, but Cesare frees her. Cornelia again rejects Tolomeo, who tries to embrace her, but Sesto bursts in sword in hand and kills him. Cesare embraces Sesto as the avenger of his father and Sesto swears allegiance to Cesare, who proclaims Cleopatra Queen of Egypt and they rejoice in their love amid general festivities.