In 1964, Gardner began his novelist career with The Liquidator, in which he created a richly comic character named Boysie Oakes who inadvertently is mistaken to be a tough, pitiless man of action and is thereupon recruited into a British spy agency. Oakes is, in actuality, a devout coward with many other character failings who wants nothing more than to be left alone and is terrified by the situations into which he is constantly being forced. The book appeared at the height of the fictional spy mania and, as a send-up of the whole business, was an immediate success. It was made into a movie by MGM of the same title, and another seven light-hearted novels about the cowardly Oakes appeared over the next 12 years.
Following the success of his Oakes books, Gardner continued to write with new characters: Derek Torry, Herbie Kruger, and the Railton family, which he intended as more serious works in the spy novel genre. Gardner also wrote three novels using the character of Professor Moriarty from the Sherlock Holmes series. The third of this series, titled simply Moriarty, was delayed due to a dispute with the publisher, but was finally released shortly after his death.
In 1981, Gardner was asked to revive Ian Fleming's James Bond series of novels. Between 1981 and 1996, Gardner wrote fourteen James Bond novels, and the novelizations of two Bond films. While the books were commercial successes, Gardner was ambivalent about writing novels with a character he hadn't created. In 1996, Gardner officially retired from writing Bond novels. Glidrose Publications quickly chose Raymond Benson to continue the literary stories of James Bond.
In the late 1990s, Gardner stopped writing for several years due to a prolonged battle with cancer and the death of his wife in 1997. Gardner recovered and returned to print in 2001 with a new novel, Day of Absolution, which was widely praised by critics. Gardner also began a series of books with a new character, Suzie Mountford, a 1930s police detective.