Elcano was born in around 1486 to Domingo Sebastián Elcano and Catalina del Puerto. He had three brothers: Domingo Elcano, a Catholic priest, Martín Pérez Elcano, and Antón Martín Elcano.
Elcano fought in the Italian Wars under the command of Gonzalo Fernández de Córdoba in Italy, and in 1509 he joined the Spanish expedition organized by Cardinal Francisco Jiménez de Cisneros against Algiers.
Elcano settled in Seville and became a merchant ship captain. After breaking Spanish laws by surrendering a ship to Genoan bankers in repayment of a debt, he sought a pardon from the Spanish king Charles V, by signing on as a subordinate officer for the Magellan expedition to the East Indies.
Elcano served as a naval commander of Charles V of Spain and took part in the expedition to the Philippines. In 1519, this 241-men expedition set sail with five ships, Trinidad, Concepción, San Antonio, Santiago, and Victoria. Elcano participated in a fierce mutiny against Magellan before the convoy discovered the passage through South America, the Strait of Magellan. He was spared by Magellan and after five months of hard labour in chains was made captain of the galleon. Santiago was later destroyed in a storm. The fleet sailed across the Atlantic Ocean to the eastern coast of Brazil and into Puerto San Julián in Argentina. Several days later they discovered a passage now known as the Strait of Magellan located in the southern tip of South America and sailed through the strait. The crew of San Antonio mutinied and returned to Spain. On 28 November 1520, three ships set sail for the Pacific Ocean and about 19 men died before they reached Guam on 6 March 1521. Conflicts with the nearby island of Rota prevented Magellan and Elcano from resupplying their ships with food and water. They eventually gathered enough supplies and continued their journey to the Philippines and remained there for several weeks. Close relationships developed between the Spaniards and the islanders. They took part in converting the Cebuano tribes to Christianity and became involved in tribal warfare between rival Filipino groups in Mactan Island.
On 27 April 1521, Magellan was killed and the Spaniards defeated by natives in the Battle of Mactan in the Philippines. The surviving members of the expedition could not decide who should succeed Magellan. The men finally voted on a joint command with the leadership divided between Duarte Barbosa and João Serrão. Within four days these two were also dead. They were killed after being betrayed at a feast at the hands of Rajah Humabon. The mission was now teetering on disaster and João Lopes de Carvalho took command of the fleet and led it on a meandering journey through the Philippine archipelago.