Early in his career, Gilbert started English settlements in Ireland (to try to stop the Irish rebellion) and, much later, sailed to North America in search of a Northwest Passage (a sea route to Asia through North America). He founded an English settlement in Newfoundland.

Gilbert is said to have believed that America was the lost continent of Atlantis (a legendary but fictional continent that is said to have sunk in ancient times). He was determined to find a sea route through the northern waters of North America. On September 23, 1578, he sailed from England, but was attacked by Spaniards and returned to England.

He successfully sailed again on June 11, 1583, with 5 ships. One ship had to return because of leaks, but the others eventually made it to North America. He landed in Newfoundland on July 30, 1583, and then sailed to St. John's. Gilbert claimed the area for Queen Elizabeth I of England, and started a colony.

After two weeks in his new colony, Gilbert left his colony to explore the area around Nova Scotia. He died on this expedition when his boat, the "Squirrel," sank near the Azore Islands on September 9, 1583 (he was returning to England). Gilbert was the step-brother of Sir Walter Raleigh.