Noted medical missionary and philanthropist, Sir Wilfred Grenfell, and his fiancée, Anne Elizabeth MacClanahan, designed the Grenfell House. Local carpenters built the structure in 1909-1910.

Grenfell first came to Newfoundland in 1892 as a part of the National Mission to Deep Sea Fishermen who came to investigate the living conditions associated with the Labrador fishery. The appalling levels of poverty endured by the fishermen and local population shocked him. The next year, he decided to return with a team of two doctors and two nurses. It was the beginning of Grenfell's lifetime of service to the people of Newfoundland and Labrador. With the assistance of the Newfoundland government, he established the first hospital on the Labrador Coast at Battle Harbour.

Initially Grenfell returned each summer and attempted to improve the plight of the coastal people and fishermen. He believed that many of the problems on the coast stemmed from the fishermen being overly dependent on the merchants. Consequently, in 1893 he helped form a fisherman's co-operative at Red Bay. By 1909, there were eight such co-operatives in operation.

Following a two-year absence from Newfoundland between 1897 and 1899, Grenfell returned and began to spend the winter months at St. Anthony. In the first winter, he supervised the construction of a hospital that opened in 1905. The same year he was responsible for the opening of the first orphanage in the area. In 1907 he was appointed a Companion of the Most Distinguished Order of St. Michael and St. George, and awarded the first Honorary Doctorate of Medicine ever granted by Oxford University. In 1909, Grenfell opened Newfoundland's first inter-denominational school and supervised the building of his own house.

The summer months were spent on fund raising and recruitment tours in England, Canada and the United States. The creation of co-operatives and the fund-raising tours brought Grenfell into conflict with the National Mission. In 1912 the conflict led to the establishment of the International Grenfell Association (IGA) with its headquarters in the United States. Grenfell modified his home in St. Anthony and allowed it to become a staff house and a dormitory for the IGA.

By 1914 the IGA administered the affairs of four hospitals and six nursing stations along the coast of Labrador and northern Newfoundland. The religious aspects of the mission became subverted to medical concerns and Grenfell continued to spend much of his time on fund-raising campaigns and recruitment drives. By the time of Grenfell's retirement in 1935, the IGA had established five hospitals, seven nursing stations and three orphanages in the region.

For all of his philanthropic work, Grenfell was knighted in 1927 the same year the IGA opened a modern hospital in St. Anthony.

His wife, Lady Grenfell, died in 1938 and Sir Wilfred died two years later. Their house is now a museum operated by the Grenfell Historical Society to honour the philanthropic work of Sir Wilfred Grenfell.

In June 1986 the Grenfell House was made a Registered Heritage Structure by the Heritage Foundation of Newfoundland and Labrador.