The impact of smallpox and other contagions on indigenous populations - originally via the ignorant carelessness of the colonizers - later either through intentional negligence and conscious intent can't be over-estimated. (Plague blankets are a fact of history - a strategy not untried on the European continent itself.)
The Fransiscan friarToribio de Benavente recorded in the early 1500s (within a generation of European contact) a drop in the indigenous population of over 50%. The conservative estimates of population decline during the 300 years after our European arrival is 90%.
That historical document is mentioned in this well-researched if tentative science article.
This extensive continent-wide surveying of mitochondrial DNA confirms a catastrophic die-off did in fact begin with European contact and spread like a bow-wave before settlement of the continent. Especially devastating effect both west and south of the Mississippi this is why settlers could stake their claims to vast empty tracts without even a twinge of minimal conscience (they were after all 'good Christian folk' claiming the land if from anyone from 'savage heathen' who 'weren't even using it anyway').
Here in British Columbia the wave hit in the late 19th century (both the coastal and inland nations having lived in effective isolation from other native nations and from Europeans to that time). Missionaries and traders recording the catastrophe write of voyages up-coast establishing trade relations with scores of villages - then discovering the same villages to be home only to ghosts the next season. The rare survivor told of the plague that carried off entire healthy ancient and affluent villages.
There's no guesswork or hyperbole in the history of the North American First Nations Apocalypse.
In the B.C. interior, where I grew up and my family pioneered, the fate of the Okanagan Salish was dramatic declining in the single generation after arrival of Europeans to the valley to 1/10th the population at first contact. Another generation and there were only a few families left - and several decades later the last full blood member of the nation passed on. My grandparents settled (with the permission of those few families) on the lush bottom land by a year-round creek traditionally used as a gathering way-station on the band's way into and down from the mountain pastures - the mid-point on their trek between seasonal permanent homes. My grandparents followed the same pattern as they drove their herds to summer in the foothills then down to winter in the valley. My grandparents watched first-hand the dwindling of a once vibrant community into that single old man - then, in the 1920s, none at all. The nation lived on by merging with a remnant of a nation in another valley.
Today, in Canada, the United Native Nations has helped to revive, sustain and regrow a new community locally and a new nation of nations across Canada.