Hopscotch is an account of the misadventures of Horacio Oliveira, a discontent Argentinean intellectual in his forties. He wanders 1950s Paris with his mistress La Maga and a band of bohemian cohorts, but a series of missteps and personal tragedies send him packing back to Buenos Aires. There, he encounters still greater tests of his sanity in the company of his childhood friend, Traveler. Hopscotch is a portrait of a creative soul stymied by an inability to act.

The story opens with Horacio searching the bridges of Paris for his mistress La Maga, who has disappeared. Horacio and Maga are members of the Serpent Club, a coterie of artists, writers, musicians, and intellectuals who convene in the evening to drink, listen to music, and engage in dialectical arguments about every facet of art and life.

Horacio lives in a small flat with Maga, but the relationship becomes horribly strained when her child, Rocamadour, comes to live with them. Horacio dissects every part of his life, and after much agonizing, he begins an affair with a wealthy Parisian, Pola, and convinces himself that Maga is sleeping with Ossip Gregorovius, another member of the Club. Eventually, he walks out on Maga, and after a long night walking in the rain - where he sees an elderly writer struck by a car - he returns home to find virtually the entire Club there. Later that night, Rocamadour dies.

Not long after, La Maga disappears. Horacio and his friend Etienne visit the old man Horacio saw struck by a car. He turns out to be Morelli, an iconoclastic writer and literary critic much beloved of the Serpent Club. That night, the Club goes to Morelli's flat to assemble his new work, a novel that can be read in any order. There, a member of the Club, Babs, attacks Horacio for what he did to La Maga. The Club disbands. Horacio retreats to a bridge, where he meets a homeless woman, Emmanuele. They have sex but are interrupted by the police, who arrest both of them.

Horacio returns to Buenos Aires, stopping at La Maga's home of Montevideo on the way. He is met in Argentina by his old friend Manolo Traveler, a worker at a circus who has never left the country. Traveler is married to a former pharmacist, Talita. He begins work as a traveling gabardine salesman, and moves in with an old girlfriend, Gekrepten, in the same hotel as the Travelers. Horacio resolves to spend more time with them, to observe their seemingly happy marriage.

Traveler gets Horacio a job with the circus, and they begin to spend most of their time together. The strong bond between Horacio and Traveler begins to put a strain on the Traveler's marriage, and Talita begins to suspect a romantic tension growing between her and Horacio.

Eventually, the owner of the circus sells it to buy a mental asylum. Traveler, Talita, and Horacio all move to the hospital to begin new jobs. While there, Horacio begins to confuse Talita with La Maga. One night, he sees her playing hopscotch in the courtyard - a game that has come to represent for him his search for an unattainable contentment. He talks to her for the first time about La Maga, and the pity she shows for him moves him to kiss her. The next morning, Traveler goes to Horacio's room to talk to him. Horacio threatens to kill himself, causing a commotion in the hospital. Traveler talks to Horacio about their relationship and Horacio's mental stability, but in the end, Horacio jumps. He survives, but all three employees are fired.