Spencer studied at the Slade School of Fine Art in London from 1908 to 1912, and he first exhibited at the New English Art Club. He frequently used his hometown, Cookham, as a setting for his paintings, many of which were based on biblical themes. From 1915 to 1918 Spencer served in World War I, an experience that inspired works such as the mural The Resurrection of the Soldiers (1928–29), in which he depicted dead soldiers emerging from their tombs into a cross-strewn landscape.

In the 1930s Spencer painted a number of erotic works on the theme of love, including Love Among the Nations (1935) and a series of highly detailed nudes of his second wife. He received harsh criticism from the Royal Academy and the public for his portrayal of St. Francis of Assisi (Francis of Assisi, Saint) in St. Francis and the Birds (1935); it was interpreted as an offensive caricature. During World War II Spencer served as an official war artist and was assigned to document the shipbuilding yards of Port Glasgow, Scotland. His experience in this working-class community inspired a new series of paintings depicting everyday life as well as biblical themes, notably The Resurrection: Port Glasgow (1947–50). Spencer reconciled with the Royal Academy and was elected a full member in 1950; he was knighted in 1959.