The characters in The General in His Labyrinth are the main character and real life leader of Gran Columbia, Simon Bolivar, mostly known in the novel as "the General"; the General's confidante and valet, or mayordomo as he is called, Jose Palacios; the General's mistress Manuela Saenz; the General's friend who has tried to assassinate him, General Francisco de Paula Santander; and another far more loyal friend to the General, Field Marshall Antonio Jose de Sucre.

The novel revolves around the last seven months of Simon Bolivar's life as he attempts to escape South America for the relative safety of Europe. He has recently resigned the presidency and his previously loyal supporters have turned against him. These really are the least of his worries. The General is dying from tuberculosis and has become a pale figure of his former self.

Even his nakedness was distinctive, for his body was pale and his face and hands seemed scorched by exposure to the weather. He had turned forty-six this past July, but his rough Caribbean curls were already ashen, his bones were twisted by premature old age, and he had deteriorated so much he did not seem capable of lasting until the following July.

On the journey he is looked after by his long time steward Jose Palacios, who still views the Genera with awe despite the fact he now has to do almost everything for him. On some days the General doesn't even have the strength to grip a cup.

On his many reflections upon life, the General states that outside of Palacios, the only person he can truly trust is his mistress, Manuela. Although she loves the General, she says that she can't go with him to Europe. Instead she will stay in Columbia and inform the General of everything that happens in his absence.

It is during his last moments with Manuela that he realizes his former supporters and friends are trying to assassinate him. It is at this point he shows how he became such a good leader, dismissing their presence outside with a wave of his hand and telling his lover to continue reading to him.

As the author states:

He had fought all his wars in the front lines, without suffering a scratch, and he had moved through enemy fire with such thoughtless serenity that even his officers accepted the easy explanation that he believed himself invulnerable.

However, his illness proves that he is far from invulnerable. The sicker he gets, the more he deteriorates, physically and mentally. At one point, the author states he is suffering from "outbursts of dementia". The novel finishes with the General dying in the half-reality half-dreamlike state he has spent most of the novel.

Then he crossed his arms over his chest and began to listen to the radiant voices of the slaves singing the six o'clock Salve in the mills, and through the window he saw the diamond of Venus in the sky that was dying forever, the eternal snows, the new vine whose yellow bellflowers he would not see bloom on the following Saturday.

Jose is so loyal to the General that after his death, the author states that in some ways he dies as well. Jose becomes an alcoholic and dies at the age of 72 on the floor of a beggar's den.