St. John's is the oldest city in North America, as indigenous tribes lived here 9,000 years ago. Vikings were the first Europeans to pass through here about 1,000 years ago, but the Italian explorer we known as John Cabot found what he called New Found Land, when he landed at the northern tip of Bonavista Peninsula on June 24, 1497 — the feast day of Saint John the Baptist.

A series of expeditions by Portuguese followed in the early 16th century, and by 1540 French, Basques and Portuguese fishermen crossed the Atlantic annually to harvest the waters off the Avalon Peninsula.

It is a common belief that St. John's name was given by Basque fishermen because the bay of St. John's is very similar to the Bay of Pasaia in the Basque Country, where one of the fishing towns surrounding it is also called San Juan.

On August 5, 1583, Sir Humphrey Gilbert claimed the area as England's first overseas colony under Royal Charter of Queen Elizabeth I. At the time, he found 16 English ships with 20 French and Portuguese vessels using the harbor. There was no permanent population, however, and Gilbert was lost at sea during his return voyage, thereby ending any immediate plans of settlement.

The resident population grew slowly in the 17th century, but St. John's was by far the largest settlement in Newfoundland when British naval officers began to take censuses around 1675. Every summer the population swelled with the arrival of migratory fishermen. In 1680, fishing ships (mostly from South Devon) set up fishing rooms at St. John's, bringing hundreds of Irish men into the port to operate inshore fishing boats.

Commercial interests, following the temporary seizure of St. John’s by the Dutch in June 1665, probably erected the town’s first significant defenses. The town was captured and destroyed three times by the French in 1696, 1705 and 1708, and twice more devastated civilian structures with fire.
 
The harbor remained fortified through most of the 18th and 19th century. The final battle of the Seven Years' War in North America (the French and Indian War) was fought in 1762 in St. John's at the Battle of Signal Hill, in which the French surrendered St. John's to the British under the command of Colonel William Amherst.

The 18th century saw major changes in Newfoundland. This time included population growth, beginnings of government and establishment of churches. At this point of history, there was also the beginning of commercial ties with North America and development of the seal, salmon and banks fisheries. St. John's grew slowly and although it was still primarily a fishing station, increasingly a commercial hub.

St. John's served as a naval base during both the American Revolutionary War and the War of 1812.

The core of the city was destroyed by fire several times, the most famous of which, the Great Fire of 1892, happened on July 8, 1892.

During the Second World War, the harbor was used by Royal Navy and Royal Canadian Navy ships used for protecting convoys. It was also the site of a large US Army base called Fort Pepperrell. This base was established as part of the "Lend-Lease" agreement between the UK and USA.