In 1519 Cano sailed as master of the Concepción, one of five vessels in Ferdinand Magellan (Magellan, Ferdinand)'s fleet, which had sailed west from Europe with the goal of reaching the Spice Islands (the Moluccas) in the East. After Magellan's death in the Philippines in April 1521, a series of men took command of the expedition, but none of them stayed in charge for longer than a few months. As one of the few remaining men, Cano took charge of one of the two surviving ships, the Victoria, later that year. He safely brought the expedition home to Spain in September 1522, despite scurvy, starvation, and harassment by the Portuguese. Only 18 Europeans had survived the voyage, which constituted the first journey around the globe.

In 1525 Cano was appointed chief pilot on García Jofre de Loaisa's expedition to claim the Molucca Islands for Spain. The expedition was ultimately a failure, though, and both Cano and Loaisa lost their lives.