When Octavian (later Augustus), Caesar's adopted son and heir, arrived in Rome, Antony joined forces with him, but they soon fell out. Antony went to take Cisalpine Gaul as his assigned proconsular province, but Decimus Brutus would not give it up, and Antony besieged him (43 b.c.) at Mutina (modern Modena). The senate, urged by Cicero, who had excoriated Antony in the Philippics, sent the consuls Aulus Hirtius and Caius Vibius Pansa to attack Antony. The consuls fell in battle, but Antony retired into Transalpine Gaul.

Octavian now decided for peace and arranged with Antony and Marcus Aemilius Lepidus the Second Triumvirate, with Antony receiving Asia as his command. In the proscription following this treaty Antony had Cicero killed. Antony and Octavian crushed the republicans at Philippi, and the triumvirate ruled the empire for five years.

In 42 b.c. Antony met Cleopatra, and their love affair began. While Antony was in Egypt, his wife, Fulvia, became so alienated from Octavian that civil war broke out in Italy. At about the time Antony arrived in Italy, Fulvia died (40 b.c.) and peace was restored between Octavian and Antony, who married Octavian's sister Octavia; she became, thereafter, Antony's devoted partisan and the strongest force for peace between the two. In 36 b.c., Antony undertook an invasion of Parthia. The war was costly and useless, and Antony succeeded only in adding some of Armenia to the Roman possessions.

In 37 b.c., Antony settled in Alexandria as the acknowledged lover of Cleopatra. He gave himself up to pleasure, caring neither for the growing ill will in Rome nor for the increasing impatience of Octavian. In 32 b.c. the senate deprived Antony of his powers, thus making civil war inevitable. In 31 b.c., Antony and his fleet met Marcus Vipsanius Agrippa with Octavian's fleet off Actium, and Antony found his large, cumbersome galleys were no match for the swift, small craft that Octavian had built. In the middle of the battle Cleopatra retired with her boats, and Antony followed her. His navy surrendered to Octavian.

The situation of the two lovers was desperate. Returning to Alexandria, they set about fortifying Egypt against Octavian's arrival. When at length Octavian did come (30 b.c.), Antony committed suicide, under the impression, it is said, that Cleopatra had died already. She killed herself soon afterward. Shakespeare's Antony and Cleopatra. is by far the best known of the many dramas on that tragedy.