The opera is based on historical events from the Roman civil war of 48 – 47 BC. Julius Caesar (Giulio Cesare) has defeated his rival Pompey (Pompeo) and pursues him to Alexandria, the capital of Egypt. There, Cleopatra and her younger brother Ptolemy XIII (Tolomeo) rule the kingdom jointly; they are the last representatives of the dynasty founded after the conquest of Egypt by Alexander the Great. Pompey seeks refuge and military support from Ptolemy.

Act I

Giulio Cesare enters Alexandria with his general Curio and his troops. There, Cornelia and Sesto, the wife and son of Pompeo, plead for peace. Cesare agrees and declares himself willing to pardon Pompeo. At that moment, Tolomeo’s advisor and general Achilla appears, presenting Pompeo’s severed head. Horrified, Cesare rejects this “gift” and resolves to confront Tolomeo that very evening.

In the Alexandrian palace, Cleopatra is determined to seize power for herself. When her servant Nireno informs her of Pompeo’s murder, she decides to seek out Cesare and win his support. Achilla reports Cesare’s reaction to Tolomeo and offers to assassinate Cesare – if he is rewarded with Cornelia’s hand in marriage.

In Cesare’s camp, funeral rites are held for Pompeo. Cleopatra appears in disguise as “Lidia,” one of her own attendants, and immediately captivates Cesare. Meanwhile, Cornelia and her son Sesto resolve to kill Tolomeo, the murderer of her husband, and Cleopatra offers them her support. Cesare meets Tolomeo in a diplomatic encounter. Despite mutual mistrust, he accepts Tolomeo’s invitation to stay in the royal palace. As will later become clear, this is a trap: Tolomeo intends to have him murdered there. Cornelia and Sesto arrive at the palace and accuse Tolomeo of responsibility for Pompeo’s death. Tolomeo is captivated by Cornelia’s beauty, but when Sesto challenges him to combat, he orders the arrest of both mother and son. Achilla promises Cornelia her freedom if she yields to him, but she indignantly refuses.

Act II

At the palace, Cleopatra – still disguised as “Lidia” – stages a performance to win Cesare completely. In it, she presents herself as the Goddess of Virtue, surrounded by the nine Muses. Cesare is enchanted. Nireno informs him that “Lidia” returns his feelings and awaits him later in her chambers.

Meanwhile, Cornelia laments her fate as a prisoner. She again rejects Achilla, only to be harassed by Tolomeo shortly thereafter. In her despair, she contemplates suicide, but is prevented by the sudden arrival of Sesto, who has escaped with the help of Nireno, Cleopatra’s servant. Nireno proposes smuggling Sesto into Tolomeo’s harem, where the king – unguarded and vulnerable – can be assassinated.

Cleopatra awaits Cesare in her chambers. But their meeting is interrupted by Cesare’s general Curio, who reports that assassins are searching the palace for him. Cleopatra reveals her true identity and urges Cesare to flee to safety. He refuses, determined to face his enemies. Cleopatra prays to the gods to protect him – and her now genuine love.

Act III

Tolomeo, feeling secure in his chambers, lays aside his weapons. Sesto attempts to kill him with his own sword but is disarmed by Achilla, who then calls Tolomeo to arms and reports that Cesare has drowned during an attack in the harbor.

Cleopatra has fled to the Roman camp and assembled an army to attack the palace. Tolomeo prepares for battle but refuses to grant Achilla the promised hand of Cornelia. Enraged, Achilla changes sides and joins Cleopatra. In the ensuing battle, however, Tolomeo’s forces prevail, and Cleopatra is taken prisoner.

Meanwhile, the sea casts the living Cesare ashore. Sesto and Nireno encounter the mortally wounded Achilla. Before dying, he gives Sesto a seal granting command over his troops. Cesare overhears this, takes the seal, and gathers an army to attack the palace. In captivity, Cleopatra prepares for suicide – but Cesare storms the palace and frees her. He sends her to the harbor to rally her forces while he himself challenges Tolomeo to combat.

Tolomeo, already convinced of his victory, continues to pursue Cornelia – until Sesto appears and kills him. The war is decided. Cesare crowns Cleopatra as the sole Queen of Egypt. She declares her loyalty to the Roman Empire. Together, the lovers celebrate peace, and all rejoice in a new beginning.