After taking a medical degree in 1696 at the University of St. Andrews, Arbuthnot became a fellow of the Royal Society in 1704 and was one of Queen Anne's physicians from 1705 until her death. Though he published mathematical and other scientific works, his fame rests on his reputation as a wit and on his satirical writings. The most important of the latter fall into two groups. The first consists of a political allegory dealing with the political jockeying of the British, French, Spanish, and Dutch that led up to the Treaty of Utrecht (1713). Published in five pamphlets, the earliest appearing in 1712, it was collected in 1727 under the composite title Law is a Bottom-less Pit; or, The History of John Bull, and it established and popularized for the first time the character who was to become the permanent symbol of England in cartoon and literature. An edition by A.W. Bower and R.A. Erickson was published in 1976.

The other satire in which Arbuthnot had an important share was the Memoirs of Martinus Scriblerus, a mocking exposure of pedantry, first published in the 1741 edition of Pope's works but largely written as early as 1713–14 by the members of the Scriblerus Club. The other members of the club acknowledged Arbuthnot as the chief contributor and guiding spirit of the work. Arbuthnot was indifferent to literary fame, and many of his witticisms and ideas for satires were later developed by and credited to his more famous literary friends.