He was educated at the College of Braine-leComte, and in 1858 he joined the Society of the Sacred Hearts of Jesus and Mary (Picpus Fathers) at Leuven. In place of his brother, Father Pamphile, who had been stricken by illness, he went as a missionary to the Sandwich (Hawaiian) Islands in 1863. He reached Honolulu in 1864 and was ordained a priest the same year. Moved by the miserable condition of the lepers (leprosy), whom the Hawaiian government deported to Kalaupapa on Molokai Island (1873), he volunteered to take charge of the settlement. He served as pastor and physician, improved water and food supplies and housing, and founded two orphanages, receiving help from other priests for only 6 of his 16 years on Molokai. In 1884 he contracted leprosy and refused cure because it would have necessitated his leaving the lepers. His remains were transferred to Leuven in 1936.

Rumours before and after Damien's death accused him of immorality, but he was exonerated by an investigation held shortly after his death. In 1965 Hawaii placed a statue of him in the National Statuary Hall of the U.S. Capitol in Washington, D.C.