During his lifetime, England and Spain were bitter rivals. Seeing Spain amassing a vast empire to the west, Queen Elizabeth I of England sent Drake on a mission to explore and to seek treasure and spices. This meant that the explorer would have to harass England's rivals in Spanish-held territory. He set sail from England in [1577] with 165 crewmen and five ships, the Pelican (later renamed the Golden Hind), the Marigold, the Elizabeth, the Swan, and the Christopher. Like Magellan, Drake and his crew suffered hardships such as storms at sea, starvation, illness, and attempted mutinies.

He abandoned two of his ships off the coast of South America and was separated from the other two ships in the Straits of Magellan. He was able to establish that the Tierra del Fuego area was an island and not a continent, as many Europeans believed following Magellan's expedition. Drake plundered Spanish shipping in the Caribbean and in Central America and loaded his ship with treasure to take back to Queen Elizabeth.

In June, 1579, Drake landed off the coast of present-day California and sailed as far north as the area that would become the United States-Canadian border. He then turned southwest and crossed the Pacific Ocean in two months time. It took another year to make his way through the Indies, across the Indian Ocean, around the Cape of Good Hope and back to England. Upon arrival, the queen knighted Drake aboard the Golden Hind.