《安东尼与克莉奥佩特拉》写于1607—1608年之间，是莎士比亚成熟期的著名悲剧。
故事发生在公元前的罗马和埃及。当时的罗马三维鼎立，由凯撒，安东尼和莱必多斯共同执政。管理东方行省的罗马大将安东尼迷恋于埃及女王克莉奥佩特拉，整日在里山大里亚安享太平，纵酒宴饮。庞贝向罗马进攻和他的妻子富尔维亚死去的消息传来，警醒了安东尼，他率领部将爱诺巴勃斯等回到了罗马。
在罗马，三执政暂时弥合分歧，重新结成了联盟。安东尼娶凯撒之妹为妻。接着三执政又同庞贝议和，他们在庞贝的船上共同进宴。席间，庞贝的部下茂那斯曾策划谋害罗马三雄，这一计划却遭到了庞贝的拒绝。
安东尼和奥克泰维娅到雅典后，从罗马传来凯撒背信弃义撕毁协议，重新向庞贝开战的消息，接着，凯撒又暗杀了庞贝，拘捕了莱必多斯。
局势的变化，安东尼又返回埃及。凯撒吞并了莱必多斯和庞贝的势力之后，又寻机向安东尼展开进攻。双方在阿克兴海峡摆开战场。此时，安东尼不听部下忠告，不顾自己善于陆战的有利条件，竟然同意和凯撒进行海战。结果，阿克兴海战遭到了惨败。
安东尼的佐将爱诺巴勃斯见大势已去，投奔了凯撒，安东尼宽恕了他，爱诺巴勃斯惭愧的结束了自己的生命。在埃及境内的战斗中，由于埃及舰队叛变，安东尼的部队又一次失败了。由于害怕安东尼对自己的惩罚，克莉奥佩特拉躲进了陵墓，并派人向安东尼谎称她已死去。安东尼闻讯决定追随女王而去。他命令忠实的部将爱洛斯把自己刺死，爱洛斯不忍下手，自刎而亡。安东尼大恸，随即自杀。临死前，他得知真情，请人将他抬到女王的陵墓，在女王的怀中闭上了眼睛。
胜利了的凯撒召见女王，一面表示愿意保护她得生命安全，一面策划将她作为战利品带回罗马。克莉奥佩特拉不愿做命运的奴仆，坦然的换上了皇袍，在毒蛇的一吻中，安然死去。

Act I
Act one is an amalgam of early 20th century New Jersey and the dawn of the Ice Age. The father is inventing things such as the lever, the wheel, the alphabet, and multiplication tables. The family (the Antrobuses) and the entire north-eastern U.S. face extinction by a wall of ice moving southward from Canada. The story is introduced by a narrator and further expanded by the family maid, Sabina. There are unsettling parallels between the members of the Antrobus family and various characters from the Bible. In addition, time is compressed and scrambled to such an extent that the refugees who arrive at the Antrobus house seeking food and fire include the Old Testament judge Moses, the ancient Greek poet Homer, and women who are identified as Muses.
Act II
Act II takes place on the Boardwalk at Atlantic City, New Jersey, where the Antrobuses are present for George's swearing-in as president of the Ancient and Honorable Order of Mammals, Subdivision Humans. Sabina is present, also, in the guise of a scheming beauty queen, who tries to steal George's affection from his wife and family. Although the conventioneers are rowdy and partying furiously, there is an undercurrent of foreboding, since the weather signals change from summery sunshine to hurricane to deluge. (A fortune teller had previously attempted to warn them about this but had been ignored). Gladys and George each attempt their individual rebellions, and are brought back into line by the family. The act ends with the family members reconciled and, paralleling the Bibilical story of Noah's Ark, directing pairs of animals to safety on a large boat where they survive the storm and/or the end of the world.
Act III
The final act takes place in the ruins of the Antrobuses' former home. A devastating war has occurred; Maggie and Gladys have survived by hiding in a cellar. When they come out of the cellar we see that Gladys has a baby. Sabina joins them, "dressed as a Napoleonic camp-follower". George has been away at the front lines leading an army. Henry also fought, on the opposite side, and returns as a general. The family members discuss the ability of the human race to rebuild and continue after continually destroying itself. The question is raised, 'is there any accomplishment or attribute of the human race of enough value that its civilization should be rebuilt'?
The stage manager interrupts the play-within-the-play to explain that several members of their company can't do their parts because they're sick (possibly with food poisoning: the actress playing Sabina claims she saw blue mold on the lemon meringue pie at dinner). The stage manager drafts a janitor, a dresser, and other non-actors to fill their parts, which involve quoting philosophers such as Plato and Aristotle to mark the passing of time within the play.
The alternate history action ends where it began, with Sabina dusting the living room and worrying about George's arrival from the office. Her final act is to address the audience and turn over the responsibility of continuing the action, or life, to them.