St. Anthony was visited by explorer Jacques Cartier in 1534 and it was already established as a summer fishing room by the French. This continued until the 1800's, when it is believed the area was permanently settled by the Patey and Simms families. The first census was taken in 1857, and it showed a population of 71, due to residents moving from the East Coast and the migration to the French Shore.
St. Anthony became the largest year-round community in the area with a population of 139 in 1891. In 1900, Dr. Wilfred Grenfell chose St. Anthony as the site for a hospital to serve northern Newfoundland and eventually moved the headquarters of the International Grenfell Association there. In 1927, a marine railway and a dry dock were built, but St. Anthony still was an important fishing town. In the 1930s, a salt fish plant was constructed by A.H. Murray and Company and in the 1940's one of the province's first cold storage fish plants was built by Job Brothers.
An American radar site was built there in 1951 and by 1962, 250 American servicemen were stationed in St. Anthony. It was incorporated as a town in 1945. St. Anthony was connected by road to the rest of the province. Along with an increase in population due to the resettlement program, the community established itself as the major service for this area.
In the 1970s, tourism began to be an important industry for the because of the near by L'Anse aux Meadows National Historic Park and its connection with Sir Wilfred Grenfell.