Antony and Cleopatra was probably completed by the end of 1606 and perhaps performed at court over Christmas of that year. When it was first performed at the Globe remains uncertain, since the public theatres remained closed for long periods in 1607 as a result of plague. It is possible, though not certain, however, that Samuel Daniel was influenced by having seen a production of Shakespeare's Antony and Cleopatra in writing his own Cleopatra (1607), which describes Cleopatra raising Antony to the monument thus:

The detail of this description, as Joan Rees points out, comes neither from Plutarch nor from Shakespeare's text, but perhaps hints at a visual memory of this difficult scene (4.15) in performance.

Like Timon of Athens and Julius Caesar, Antony and Cleopatra returns to Plutarch for its source material, focusing on the figure of Antony, who not only appears in more than one of Plutarch's Lives, and whose own life was already a source for Timon, but whom Shakespeare had already dramatised once in Julius Caesar. And like all the tragedies from Timon onwards, it seems to resonate with topical allusion, especially to court matters. James I's liking for parallels drawn between himself and the Emperor Augustus (the later title of Octavius Caesar in the play) was well known, and, at a more critical level, the extravagance of Antony and Cleopatra may have seemed to contemporary audiences reminiscent of the kind of spending for which the Jacobean court had become notorious.