The novel is narrated by Alexias, a noble Athenian youth, who becomes a noted beauty in the city and a champion runner. The novel suggests that young male Athenians were treated almost like modern debutantes and wooed by older men seeking to be their lovers; in fact, in a memorable passage, Alexias' father, Myron, himself a former beauty and champion athlete, writes to his son before leaving Athens for the Sicilian Expedition. The father imparts to the son the traits he should seek in a lover– qualities like honor, loyalty and courage. However, the father also warns the son not to become involved with women as he is much too young. (See Athenian pederasty.)
As an Ephebe (adolescent male), Alexias falls in love with Lysis, a man in his 20s– a champion pankratiast and a student of Socrates. The novel follows their relationship through the Peloponnesian War, the surrender of Athens, the establishment of the Thirty Tyrants rule over Athens, the democratic rebellion of Thrasybulus and shortly after. The story ends with first hints of the eventual trial of Socrates for teaching blasphemy and sowing social disorder.
From the beginning of the novel, Socrates figures prominently; both Alexias and Lysis become his students in their youth. Socrates was very prominent around the city, always talking to new people. Also characterized in the novel are Plato and several figures from his Dialogues who were Socrates' students, including Xenophon, Crito and Phaedo. Another historical figure who figures in the story, albeit mostly off-stage, is Alcibiades, the Athenian general who flees Athens on a charge of sacrilege and functions as a military adviser to Sparta until he is recalled by a resurgent democracy in Athens. Alexis and Lysis serve under Alcibiades' command until his carelessness leads the fleet to disaster and he once again goes into exile.
In the course of the novel, Lysis falls in love with and marries a woman who sees Alexias favorably and encourages the continuation of her husband's relationship with him. Not long after this, Athens is defeated by Sparta in the Peloponnesian War. Alexias' father is murdered under the Spartan-installed tyranny, and he and Lysis go into exile in Thebes joining Thrasybulus when he leads the next democratic revolt. Lysis is killed in the battle between the Long Walls running from the port of Piraeus to Athens (the Battle of Munychia). Shortly after the victory, Alexias takes Lysis' widow under his protection, marries her and continues his family line. The book ends with the postscript that this story (incomplete and long-forgotten) has been found by Alexias' grandson (also named Alexias), a commander of Athenian cavalry in the service of Alexander the Great.