McLoughlin was hired as a physician at Fort William, the inland headquarters and a fur trade post of the North West Company on Lake Superior.[when?]

The Hudson's Bay Company was found culpable by the appointed Royal Commissioner at its trial on October 30, 1818, and in the later prosecutions by Lord Selkirk and the successful counter-suits.

The York Factory Express trade route had evolved from an earlier express brigade used by the North West Company between Fort George, founded in 1811 by John Jacob Astor's American Fur Company) at the mouth of the Columbia River, to Fort William on Lake Superior.

[4] George Simpson, Governor of Hudson's Bay Company, visited the Columbia District in 1824–25, journeying from York Factory.

It was the nexus for the fur trade on the Pacific Coast; its influence reached from the Rocky Mountains to the Hawaiian Islands, and from Russian Alaska into Mexican-controlled California.

John McLoughlin was worried Fort Vancouver would be attacked and plundered of its heavy stock of supplies, due to its proximity to the Willamette Valley, in which there was already an American settlement of some size.

Each brigade consisted of about forty to seventy-five men and two to five specially made boats that traveled at breakneck speed (for the time).

The brigades used boat, horseback, and backpacks to bring the supplies in and furs out to the forts and trading posts along the route.

Apprehensions about American antagonism rose due to US Senator Lewis F. Linn, who in 1838 called for a naval force to be dispatched to the Columbia River, although the measure never passed.

McLoughlin criticized the idea of a fur trading monopoly maintaining agricultural operations, as he felt independent farmers would be efficient.

[9] In November 1839, Sir George Simpson instructed Duncan Finlayson to begin promoting the PSAC among the Red River colonists.

[12] When three Japanese sailors, among them Otokichi, were shipwrecked on the Olympic Peninsula in 1834, McLoughlin thought they might present an opportunity to open trade with Japan.

In 1821, with the merger of HBC and the North West Company, the British Parliament imposed the laws of Upper Canada on British subjects in Rupert’s Land and the Columbia District, and gave the authority to enforce those laws to the newly reconfigured Hudson's Bay Company.

In August 1828, McLoughlin was in charge at Fort Vancouver when American explorer Jedediah Smith, John Turner, Arthur Black, and Richard Leland arrived, the only survivors of the massacre of fifteen members of his exploring party by Umpqua people, who lived to the south in Oregon.

[15] In the early 1840s, with the arrival of the first wagon trains via the Oregon Trail, McLoughlin disobeyed company orders and extended substantial aid to the American settlers.

As tensions mounted in the Oregon boundary dispute; Simpson, realizing that border might ultimately be as far north as the 49th parallel, ordered McLoughlin to relocate their regional headquarters to Vancouver Island.

McLoughlin, in turn, directed James Douglas to construct Fort Camosun (now Victoria, British Columbia, Canada) in 1843.

[19] McKay was the daughter of Jean-Étienne Waddens, who was one of the original partners of the North West Company, and an indigenous woman whose name is unknown.

[19] McLoughlin's appearance, 6 foot 4 inches (193 cm) tall with long, prematurely white hair, brought him respect; but he was also generally known for his fair treatment of the people with whom he dealt, whether they were British subjects, U.S. citizens, or of indigenous origin [citation needed] (notwithstanding for example, his asymmetric use of force against the S'Klallam tribe after an earlier raid--an HBC ship under his command fired its cannons into an unrelated village near Port Townsend in the early morning, killing twenty-seven people and leveling the village.

After resigning from the Hudson's Bay Company in 1846, McLoughlin moved his family south to Oregon City in the Willamette Valley.

[23] McLoughlin is featured on the 1925 Fort Vancouver Centennial half dollar designed by Laura Gardin Fraser.

In 1953, the state of Oregon donated to the National Statuary Hall Collection a bronze statue of McLoughlin, which is currently displayed at the Capitol Visitor Center.