An unordained Anglican minister at the age of 25, he was sent to British Columbia by the Church Missionary Society of England in 1857 to work among the Tsm'shians at Fort Simpson. After five years, during which time he learned the Tsimshian language (Shm'algyack) with amazing facility, Duncan left with a handful of followers to establish Metlakatla, a sanctuary where they could live and work away from the corrupting influences of the new white society. Within a few months, hundreds more joined the community, looking to Duncan for help from a devastating smallpox epidemic.

With Duncan in firm command, but working skillfully through the native leaders, Metlakatla prospered and became a world-famous showplace. But things never went smoothly for the combative Duncan. He became embroiled in biter disputes with Governor James Douglas, Bishop George Hills and Prime Minister John A. Mcdonald, among others. He was an outspoken advocate of Indian rights, particularly land ownership, when that was not a popular cause among the land-seeking white population.