Traditionally, this site has been the collective winter village of the "Nine Tribes" of the lower Skeena River, which since 1834 have been mostly based at Lax Kw'alaams, B.C.

In 1862, the Anglican lay minister William Duncan established at Metlakatla a utopian Christian community, made up of about 350 Tsimshian from Lax Kw'alaams (a.k.a.

Duncan used the epidemic to proselytize, saying that the disease had been sent by God as a punishment for the sins of the Tsimshian, and that those who repented and "came to Jesus" and were baptized would be spared.

Duncan's own style, in the image of which the new community was shaped, was a dissident, evangelical form of low-church Anglicanism that omitted the sacrament of communion.

In November 2016, a study published in Nature Communications linked the genome of 25 Indigenous people who inhabited modern-day Prince Rupert, British Columbia 1000 to 6000 years ago with their descendants in the Metlakatla First Nation.