In 1816 McLoughlin was arrested for the murder of Robert Semple, the governor of the Red River colony, though it is claimed he stood in proxy for some Indians who were blamed. He was tried on October 30, 1818, with the charges being dismissed. McLoughlin helped negotiate the merger between the Northwest Fur Company and the Hudson's Bay Company.
In 1824 McLoughlin was appointed Chief Factor of the Columbia District. Peter Skein Ogden was appointed to assist him. McLoughlin concluded upon his arrival that Fort Astoria was unfit for a headquarters. He built a new fort at Bell Vue Pt. and named it Fort Vancouver. Ft. Vancouver was blessed by being at the confluence of three rivers; the Columbia, the Willamette, and the Cowlitz. The post was opened for business on March 19, 1825.
McLoughlin was known for his fair treatment of everyone, whether British citizens, Americans, and Native Americans. Many Hudson's Bay field employees had native wives, including McLoughlin's wife Marguerite. The Columbia District was very profitable for Hudson's Bay during these years, due to McLoughlin's management and the popularity in Europe of hats made from beaver.
In 1841, with the arrival of the first wagon train, McLoughlin disobeyed company orders and extended aid to the American settlers. Relations between Britain and the United States were very strained at that time, and many expected war to break out any time. McLoughlin's aid probably prevented an armed attack on his outpost by the American settlers. However, the settlers understood that his motives were not purely altruistic, and some resented him and worked against him for the rest of his life. The Hudson's Bay Company eventually realized that the increasing numbers of American settlers would result in Ft. Vancouver being on US Territory, and ordered McLoughlin to move everything to Vancouver Island. This new fort was named Adelaide, which became the modern city of Victoria, British Columbia in Canada.
After retiring from the Hudson's Bay Company in 1846, McLoughlin moved his family to Oregon City. His store, where he sold food and farming tools to settlers, became the last stop on the Oregon Trail. In 1847, McLoughlin was given the Knighthood of St. Gregory, bestowed on him by Pope Gregory. He became a US Citizen in 1849. McLoughlin's opponents succeeded in inserting a clause forfeiting his land claim in the Donation Land Act of 1850, and though it was never enforced it embittered the elderly McLoughlin. He served as mayor of Oregon City in 1851, winning 44 of 66 votes, and died of natural causes on September 3, 1857.