The name in the Woods Cree language originally referred only to the Peace–Athabasca Delta formed by the confluence of the Peace and Athabasca rivers at the southwest corner of the lake.

[9][10] In 1791, Philip Turnor, cartographer for the Hudson's Bay Company, wrote in his journal, "low swampy ground on the South side with a few willows growing upon it, from which the Lake in general takes its name Athapison in the Southern Cree tongue which signifies open country such as lakes with willows and grass growing about them".

In the era of the North American fur trade, the lake was a pivotal point, since it was as far west as canoes could travel from the east and still return before freeze-up.

The first European settlement on Lake Athabasca is Fort Chipewyan, founded as a North West Company (NWC) trading post in 1788.

[5][8] In fall 1790, Malcolm Ross, Peter Fidler, Philip Turnor, and others, all working for the Hudson's Bay Company (HBC), travelled from Cumberland House to Île-à-la-Crosse, and on to Lake Athabasca the following spring.

The large oil sands mining nearby is suspected to have added to the current pollution levels in the lake.

[18] On October 31, 2013, one of Obed Mountain coal mine's pits failed, and between 600 million and one billion litres of slurry poured into the Plante and Apetowun Creeks.