Brisbane entered the army in 1789 and served in Flanders, the West Indies, Canada, and Spain. (His military services were rewarded with a knighthood in 1814.) He first decided to master astronomy in 1795, when a navigational error almost resulted in a shipwreck on his first voyage to the West Indies. In 1821 he was appointed governor of New South Wales, and, although generally a poor administrator, he systematized the administration of the convict system, hiring out convicts to settlers for clearing land. He also reformed the currency and abolished censorship of the press. He established the observatory at Parramatta in 1822 and upon his return to Scotland in 1826 built the observatory at Makerstoun, where he did astronomical work until 1847.

Brisbane was awarded the gold medal of the Royal Astronomical Society in 1828 and was elected president of the Royal Society of Edinburgh in 1833. He was made a baronet in 1836 and attained the rank of general in 1841. His middle name, Makdougall, was his wife's maiden name, which he added to his own in 1826.