Cayo Guillermo is a kay of the Jardines del Rey archipelago. It is located on the northern coast of Cuba, between the Bay of Dogs (Bahia Perros) and the Atlantic Ocean.

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It is part of the Ciego de Ávila Province, and lies in the Morón municipality. The island is a popular tourist destination, with four all-inclusive resorts located on the north side of the island: Gran Caribe Villa Cojimar, Iberostar Daiquiri, Melia Cayo Guillermo and the Sol Cayo Guillermo. Two of the hotels are owned by the Sol Melia Group. Just east of the resorts by the causeway to Cayo Coco is a marina used by yachts, sport fishing and tour boats. One of the country's best beaches, the Playa Pilar (Pilar Beach) is located at the western end of Cayo Guillermo. This beach is named after Ernest Hemingway's yacht, the cabin cruiser Pilar. The island provides the setting for the climax of Hemingway's last novel Islands in the Stream

Access to the island is possible through the Jardines del Rey Airport (Aeropuerto Jardines del Rey) (IATA: CCC, ICAO: MUCC) as well as by means of a long causeway from mainland Cuba to Caya Coco leading to a second shorter causeway to Cayo Guillermo, connecting the two kays.