The story centers on a friendship between Gilgamesh and Enkidu. Enkidu is a wild man created by the gods as Gilgamesh's equal to distract him from oppressing the people of Uruk. Together, they journey to the Cedar Mountain to defeat Humbaba, its monstrous guardian. Later they kill the Bull of Heaven, which the goddess Ishtar sends to punish Gilgamesh for spurning her advances. As a punishment for these actions, the gods sentence Enkidu to death.

The second half of the epic focuses on Gilgamesh's distress at Enkidu's death, and his quest for immortality. In order to learn the secret of eternal life, Gilgamesh undertakes a long and perilous journey. He learns that "The life that you are seeking you will never find. When the gods created man they allotted to him death, but life they retained in their own keeping."