The plot is based on Thomas North's translation of Plutarch's Life of Markus Antonius and follows the relationship between Cleopatra and Mark Antony from the time of the Parthian War to Cleopatra's suicide. The major antagonist is Octavius Caesar, one of Antony's fellow triumvirs and the future first emperor of Rome. The tragedy is a Roman play characterized by swift, panoramic shifts in geographical locations and in registers, alternating between sensual, imaginative Alexandria and the more pragmatic, austere Rome. Many consider the role of Cleopatra in this play one of the most complex female roles in Shakespeare's work. She is frequently vain and histrionic, provoking an audience almost to scorn; at the same time, Shakespeare's efforts invest both her and Antony with tragic grandeur. These contradictory features have led to famously divided critical responses.
Modern editions divide the play into a conventional five act structure, but as in most of his earlier plays, Shakespeare did not create these act divisions. His play is articulated in forty separate 'scenes', more than he used for any other play. Even 'scenes' may be inappropriate a description, as the scene changes are often very fluid, almost montage-like. The large number of scenes are necessary because the action frequently switches between Alexandria, Italy, Messina in Sicily, Syria, Athens and other parts of Egypt and the Roman Empire. The play contains thirty-four speaking characters, fairly typical for a Shakespeare play on such an epic scale.
Octavius calls Antony back to Rome from Alexandria in order to help him fight against Pompey (Sextus Pompeius), Menecrates, and Menas, three notorious pirates of the Mediterranean. At Alexandria, Cleopatra begs Antony not to go, and though he repeatedly affirms his love for her, he eventually leaves.
Back in Rome, Agrippa brings forward the idea that Antony should marry Octavius Caesar's sister, Octavia, in order to cement the bond between the two men. Antony's lieutenant Enobarbus, though, knows that Octavia can never satisfy him after Cleopatra. In a famous passage, he delineates Cleopatra's charms in paradoxical terms: "Age cannot wither her, nor custom stale / Her infinite variety: other women cloy / The appetites they feed, but she makes hungry / Where most she satisfies."
A soothsayer warns Antony that he is sure to lose if he ever tries to fight Octavius.
In Egypt, Cleopatra learns of Antony's marriage, and takes furious revenge upon the messenger that brings her the news. She grows content only when her courtiers assure her that Octavia is homely by Elizabethan standards: short, low-browed, round-faced and with bad hair.
At a confrontation, the triumvirs parley with Pompey, and offer him a truce. He can retain Sicily and Sardinia, but he must help them "rid the sea of pirates" and send them tributes. After some hesitation Pompey accedes. They engage in a drunken celebration on Pompey's galley. Menas suggests to Pompey that he kill the three triumvirs and make himself ruler of Rome, but he refuses, finding it dishonorable. Later, Octavius and Lepidus break their truce with Pompey and war against him. This is unapproved by Antony, and he is furious.
Antony returns to Alexandria, Egypt, and crowns Cleopatra and himself as rulers of Egypt and the eastern third of the Roman Empire (which was Antony's share as one of the triumvirs). He accuses Octavius of not giving him his fair share of Pompey's lands, and is angry that Lepidus, whom Octavius has imprisoned, is out of the triumvirate. Octavius agrees to the former demand, but otherwise is very displeased with what Antony has done.
Antony prepares to battle Octavius. Enobarbus urges Antony to fight on land, where he has the advantage, instead of by sea, where the navy of Octavius is lighter, more mobile and better manned. Antony refuses, since Octavius has dared him to fight at sea. Cleopatra pledges her fleet to aid Antony. However, in the middle of the battle, Cleopatra flees with her sixty ships, and Antony follows her, leaving his army to ruin. Ashamed of what he has done for the love of Cleopatra, Antony reproaches her for making him a coward, but also sets this love above all else, saying "Give me a kiss; even this repays me."
Octavius sends a messenger to ask Cleopatra to give up Antony and come over to his side. She hesitates, and flirts with the messenger, when Antony walks in and angrily denounces her behavior. He sends the messenger to be whipped. Eventually, he forgives Cleopatra, and pledges to fight another battle for her, this time on land.
On the eve of the battle, Antony's soldiers hear strange portents, which they interpret as the god Hercules abandoning his protection of Antony. Furthermore, Enobarbus, Antony's long-serving lieutenant, deserts him and goes over to Octavius's side. Rather than confiscating Enobarbus's goods, which he did not take with him when he fled to Octavius, Antony orders them to be sent to Enobarbus. Enobarbus is so overwhelmed by Antony's generosity, and so ashamed of his own disloyalty, that he dies from a broken heart.
The battle goes well for Antony, until Octavius shifts it to a sea-fight. Once again, Antony loses when Cleopatra's fleet deserts to Octavius's side—his fleet surrenders, and he denounces Cleopatra: "This foul Egyptian hath betrayed me." He resolves to kill her for the treachery. Cleopatra decides that the only way to win back Antony's love is to send him word that she killed herself, dying with his name on her lips. She locks herself in her monument, and awaits Antony's return.
Her plan fails: rather than rushing back in remorse to see the "dead" Cleopatra, Antony decides that his own life is no longer worth living. He begs one of his aides, Eros, to run him through with a sword, but Eros cannot bear to do it, and kills himself. Antony admires Eros' courage and attempts to do the same, but only succeeds in wounding himself. In great pain, he learns that Cleopatra is indeed alive. He is hoisted up to her in her monument, and dies in her arms.
Octavius goes to Cleopatra, trying to convince her to surrender. She angrily refuses, since she can imagine nothing worse than being led in triumph through the streets of Rome, proclaimed a villain for the ages. She imagines that "the quick comedians / Extemporally will stage us, and present / Our Alexandrian revels: Antony / Shall be brought drunken forth, and I shall see / Some squeaking Cleopatra boy my greatness / I' th' posture of a whore." This speech is full of dramatic irony, because in Shakespeare's time Cleopatra really was played by a "squeaking boy", and Shakespeare's play does depict Antony's drunken revels.
Cleopatra is betrayed and taken into custody by the Romans. She tests Octavius' intentions towards her by instructing her treasurer to 'betray' her when she gives Octavius an accounting of her wealth. When Octavius dismisses his statement that Cleopatra has held back information about her actual possessions Cleopatra realises that, despite his promises of fair treatment, he intends to parade her at his triumph.
Cleopatra resolves to kill herself, using the poison of an asp. She dies calmly and ecstatically, imagining how she will meet Antony again in the afterlife. Her serving maids, Iras and Charmian, also kill themselves. Octavius discovers the dead bodies and experiences conflicting emotions. Antony's and Cleopatra's deaths leave him free to become the first Roman Emperor, but he also feels some kind of sympathy for them: "She shall be buried by her Antony. / No grave upon the earth shall clip in it / A pair so famous..." He orders a public military funeral.
One of the major themes running throughout the play is opposition. The main being Rome/Egypt, Love/Lust, and Male/Female. One of Shakespeare's most famous speeches, Enobarbus' description of Cleopatra on her barge, is full of opposites. Cleopatra herself sees Antony as both the Gorgon and Mars (Act 2 Scene 5, lines 118-19)