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Drake led the second expedition to sail around the world in a voyage lasting from 1577 to 1580 (Magellan led the first voyage around the world). Queen Elizabeth I commissioned Drake to command the expedition together with John Winter and Thomas Doughty. They left Plymouth, England, on December 13, 1577, with six ships (including the Golden Hind). They sailed to Brazil, and through the perilous Strait of Magellan (between August 20 and September 6, 1578). At Tierra del Fuego (located at the southern tip of South America), natives gave Drake and his crew food and water. They sailed by Panama (1579), where he pirated Spanish ships and settlements for food and treasures. He landed on the island of Cano, off the coast of southern Mexico. In North America, he claimed the land he called "Nova Albion" for the Queen (his exact location was kept secret, but he may have sailed as far north as northern California or even Vancouver Island, Canada). They then crossed the Pacific Ocean and sailed by Indonesia, through the Indian Ocean, past the Cape of Good Hope, and back to Plymouth, England, in 1580. Upon his return, the Queen rewarded Drake with a large sum of money (£10,000).

Drake was also involved in the slave trade and was a fierce warrior and privateer. Drake and John Hawkins were on a slave-trading trip to the West Indies (backed by Queen Elizabeth) that ended with an attack by the Spanish fleet at San Juan de Ulua, near Veracruz, Mexico. The six English slave-trading ships were in the harbor for repairs, and only two ships survived the attack, those commanded by Hawkins and Drake; the Spanish did not want the English competing in their highly profitable slave-trading business. This battle led to a series of battles that later resulted in a war between Spain and England. In this war, England crushed the Spanish Armada in 1588 and became the dominant world power. Drake helped the British defeat the Spanish Armada; he was second in command. The Spanish called him El Draque, meaning "The Dragon."

Drake died of fever at sea near Panama; he was on a voyage intending to attack Spanish colonies in the West Indies.