After his discharge from the military, Cussler went to work for the advertising industry, first as a copywriter and later as a creative director for two of the nation's most successful advertising agencies. As part of his duties, Cussler produced radio and television commercials, many of which won international awards including an award at the Cannes Lions International Advertising Festival.

After the publication in 1996 of Cussler's first nonfiction work, The Sea Hunters, he was awarded a Doctor of Letters degree in 1997 by the Board of Governors of the State University of New York Maritime College who accepted the work in lieu of a Ph.D. thesis. This was the first time in the college's 123-year history that such a degree had been awarded.

In 2002, Cussler was awarded the Naval Heritage Award from the U.S. Navy Memorial Foundation for his efforts concerning marine exploration. Cussler was a fellow of the Explorers Club of New York, the Royal Geographical Society in London, and the American Society of Oceanographers.

Clive Cussler began writing in 1965 when his wife took a job working nights for the local police department where they lived in California. After making dinner for the children and putting them to bed, he had no one to talk to and nothing much to do, so he decided to start writing. His most famous character is marine engineer, government agent and adventurer Dirk Pitt. The Dirk Pitt novels frequently have an alternative history premise—such as "what if Atlantis were real?" or "what if Abraham Lincoln wasn't assassinated but was kidnapped?"

The first two Pitt novels, The Mediterranean Caper and Iceberg, were relatively conventional maritime thrillers. The third, Raise the Titanic!, made Cussler's reputation and established the pattern that subsequent Pitt novels would follow: a blend of adventure and advanced technology, generally involving megalomaniacal villains, lost ships, beautiful women, and sunken treasure.

Cussler's novels almost always begin with a chapter set in the past. These contain none of the novel's main characters and often seem disconnected from the plot until the main characters discover a mystery or secret relating the events of the first chapter to the rest of the story. This is almost always in the form of a long-lost artifact that is important to the villain's or hero's objectives. Often in the first chapter, a ship or airplane carrying a top-secret, important, or dangerous cargo is lost and never found, until it is recovered by a modern character later in the book.

Cussler's novels, like those of Michael Crichton, are examples of techno-thrillers that do not use military plots and settings. Where Crichton strove for scrupulous realism, however, Cussler prefers fantastic spectacles and outlandish plot devices. The Pitt novels, in particular, have the improbable quality of the James Bond or Indiana Jones movies, while also sometimes borrowing from Alistair MacLean's novels. Pitt himself is a super-hero reminiscent of Doc Savage and other characters from pulp magazines.

Clive Cussler married Barbara Knight in 1955, and they remained married for nearly 50 years until her death in 2003. Together they had three children—Teri, Dirk, and Dayna—four grandchildren, and four great-grandchildren. Cussler's daughter Teri is the creator and manager of the Cussler Museum in Arvada, Colorado, where Cussler's collection of classic automobiles is on display. Cussler also married Janet Horvath, who survived him. Clive Cussler was a part-time resident of both Arizona and Colorado.