In the tradition of ancient Greek epics, John Milton begins his poem by calling on the guidance of a heavenly muse to help tell his tale, stating that his goal is to justify the ways of God to man. He begins his story in medias res (in the middle of things). God has cast Satan and his rebel army of fallen angels out of Heaven, and they are floating on a fiery lake in Hell. These angels become devils and form a council to debate how to overthrow God. Through his second-in-command, Satan convinces them that the best target is man, God's newest creation. Satan volunteers to fly to the world full of God's new creatures. His daughter, Sin, and their incestuous son, Death, help him escape from Hell. The personifications of Chaos and Night also help pave the way for Satan to enter the new world, because they have no particular allegiance to God.
God, in his omniscience, already knows that Satan will succeed in tempting and corrupting mankind. He announces that man will be punished for his disobedience, because he created humans to be strong enough to withstand temptation. He claims that his new creations will be punished by death unless someone in Heaven is willing to die on their behalf. Only God's Son volunteers.
Satan lands in the new world and sneaks into the Garden of Eden disguised as a cherub. Once inside the garden, he spies God's new creations, Adam and Eve, and is deeply envious of their innocence and happiness. Though he has a moment of doubt and almost feels love for the humans, he resolves to continue with his plan to corrupt them. It is the only revenge he can get against God. He overhears Adam and Eve discussing how God forbade them from eating fruit from the Tree of Knowledge and decides that he will trick them into disobeying God by eating the fruit.
Uriel, the angel guarding Paradise, realizes that the cherub is Satan in disguise and sends for the archangel Gabriel to find the intruder. Gabriel confronts him, and Satan reveals himself and prepares for battle. God then sends Satan a warning: a pair of Golden Scales in the sky that demonstrates how pointless it is to fight. Satan flees, recognizing that God does have the ultimate power and advantage.
Satan whispers an upsetting dream about eating the fruit from the Tree of Knowledge in Eve's ear while she is sleeping. God decides that although he cannot control their actions, he must warn Adam and Eve about Satan. He sends his archangel Raphael to discuss with Adam the idea that they have the free will to make their own choices and to warn them about the temptation they will face and its consequences.
Raphael also tells Adam the story of Satan's rebellion in Heaven—which began when Satan, then a high-ranking angel, became envious of the Son, who would become King of Heaven. Satan then convinced other angels to rebel against God and forms an army. Yet all angels are immortal—while they can be wounded, they can't be killed. The battle that Raphael describes to Adam seems pointless, especially because the all-powerful God can call an end to the war whenever he likes. He does so on the third day, telling his Son to banish the rebel angels to Hell.
After Raphael finishes telling Adam the story, Satan returns to the Garden of Eden, taking on the disguise of a serpent. He finds Eve alone and speaks to her. Eve is curious about how he came to be able to speak, and he tells her that he learned by eating fruit from the Tree of Knowledge. He tells her that if she eats the fruit she can become a goddess and gain knowledge as well. After hesitating, she eats the fruit and then offers it to Adam. Though he realizes that she has disobeyed God's orders, he eats the fruit so they will share the same fate.
God then sends the Son to the Garden of Eden, where he condemns Eve and all future women to experience pain when they give birth. He also condemns Adam to have to labor to grow his food and tells Eve she must submit to Adam. Satan is gleeful that he has accomplished his plan, and his children, Sin and Death, build a bridge between Hell and Earth. Though Satan arrives triumphantly in Hell, believing he has outsmarted God, God punishes Satan by turning him and the other devils into serpents, doomed to eternally hunger for fruit that turns to ashes when they bite into it.
God next orders angels to make the new world more hostile to mirror Adam and Eve's fall. The angels create storms and turn creatures against each other to create discord and suffering. Adam and Eve begin fighting and blame each other for the punishment they are enduring. Ultimately they decide to repent to God, swearing to be obedient. God agrees to be merciful, allowing them and their offspring into Heaven in the afterlife if they are obedient to him.
God sends the archangel Michael to show Adam what his and Eve's future will look like: their sons will murder each other, tyrants will rule, and biblical floods will wipe out most people. Yet he offers them hope in addition to depicting the suffering that future humans will endure: he shows Adam a rainbow meant to reflect God's mercy and biblical characters such as Noah, Enoch, and Jesus—men who will redeem humanity through their selfless acts. Adam and Eve finally leave Paradise, accepting their fate.