While still a medical student at London University in 1887, Grenfell was impressed by the sermons of the American evangelist Dwight L. Moody and, in the same year, joined the Royal National Mission to Deep Sea Fishermen. During the next five years he served as surgeon on the first hospital ship dispatched to the North Sea fisheries, and in 1892 he initiated missionary service to the fishermen of Labrador. He soon became absorbed in improving the living conditions of the inhabitants of the Labrador coast, and he undertook to raise funds from numerous speaking tours and popular books, such as Vikings of To-day (1895).

After withdrawal of the Mission's support in 1912, he founded the International Grenfell Association, with branches in England, the United States, Newfoundland, and other parts of Canada. Largely because of this organization's efforts, there existed in Labrador when Grenfell retired (1932) 6 hospitals, 4 hospital ships, 7 nursing stations, 2 orphanages, 2 large schools, 14 industrial centres, and a cooperative lumber mill. He was knighted in 1927.