Employed by Britain, Cabot searched for the Northwest passage across North America (1508). Later, for Spain, he began a trip around the world (1526-1529) in a voyage that was supposed to sail to China and the Moluccas (the Spice Islands, in Indonesia), but he only made it as far as the enormous mouth of the Rio de la Plata (a river between Argentina and Uruguay in South America). After fighting with and abandoning some of his crew, Cabot explored this river and the Paraná River (from 1526 to 1529). Hostile natives and a lack of food forced him to return to Spain. His trip was deemed unsuccessful, and he was banished from Spain to Africa for two years (this punishment was later changed to a single year of banishment).

Around 1553, Cabot began to work for the English again, searching for a water passage across the north of Asia. On this voyage, he sailed as far as the White Sea (off the Barents Sea in northwestern Russia). This expedition resulted in a successful trade agreement between England and Russia.

Very little is known about Sebastian Cabot's life; the account he wrote of his journeys has been lost - only one map that he drew (in 1544) still exists. Cabot may have made other undocumented trips, including trips to the West Indies. Some historians doubt that his 1508 journey in search of a Northwest passage across North America actually happened.