Keyhoe was born and raised in Ottumwa, Iowa. He earned a B.S. degree at the United States Naval Academy in 1919, and was commissioned a Marine Corps Lieutenant.

In 1922, his arm was injured during an airplane crash in Guam. During his long convalescence, Keyhoe began writing as a hobby. He eventually returned to active duty, but the injury gave Keyhoe persistent trouble, and, as a result, he retired from the Marines in 1923. He then worked for the National Geodetic Survey and U.S. Department of Commerce.

In 1927, Keyhoe managed a very popular coast-to-coast tour by Charles Lindbergh. This led to Keyhoe's first book, 1928's Flying With Lindbergh. The book was a quick success, and led to a freelance writing career, with many of Keyhoe's articles and fictional stories (mostly related to aviation) appearing in a variety of leading publications.

Keyhoe returned to active duty during World War II in a Naval Aviation Training Division, retiring again a Major.

By the time his UFO books appeared, Keyhoe was already a well-established author with numerous appearances in the pulp magazines of the 1920s and 30s. Four of his short stories were printed in Weird Tales, one of the most prestigious of the pulps: "The Grim Passenger" (1925), "The Mystery Under the Sea" (1926), "Through the Vortex" (1926) and "The Master of Doom" (1927). He also produced the lead novel for all three issues of a short-lived magazine called Dr. Yen Sin: "The Mystery of the Dragon's Shadow" (May/June 1936), "The Mystery of the Golden Skull" (July/August 1936) and "The Mystery of the Singing Mummies" (September/October 1936).[1]

Keyhoe wrote a number of air adventure stories, for Flying Aces and other magazines, and created two larger-than-life superheroes in this genre. The first of these was Captain Philip Strange, referred to as "the Brain Devil" and "the Phantom Ace of G.2.". Captain Strange was an American intelligence officer during World War I who was gifted with ESP and other mental powers. His existence has been perpetuated beyond Keyhoe's stories as a minor member of the Wold Newton universe.

Keyhoe's other "superpowered" flying ace was Richard Knight, a World War I veteran who was blinded in combat but gained a supernatural ability to see in the dark. Knight featured in a number of adventure stories set in the 1930s (when the stories were written).

Many of Keyhoe's stories for the pulps were science fiction or weird fantasy, or contained a significant measure of these elements —- a fact that was not lost on later critics of his UFO books.

He was also a freelancer for Saturday Evening Post, The Nation, and Reader's Digest.

Following Kenneth Arnold's report of odd, fast-moving aerial objects in the summer of 1947, interest in "flying disks" and "flying saucers" was widespread, and Keyhoe followed the subject with some interest, though he was initially skeptical of any extraordinary answer to the UFO question. For some time, True (a popular American men's magazine) had been inquiring of officials as to the flying saucer question, with little to show for their efforts. In about May 1949, after the U.S. Air Force had released contradictory information about the saucers, editor Ken Purdy turned to Keyhoe, who had written for the magazine, but who also, importantly, had many friends and contacts in the military and the Pentagon.

After some investigation, Keyhoe became convinced that the flying saucers were real. As their forms, flight maneuvers, speeds and light technology was apparently far ahead of any nation's developments, Keyhoe became convinced that they must be the products of unearthly intelligences, and that the U.S. government was trying to suppress the whole truth about the subject. This conclusion was based especially on the response Keyhoe found when he quizzed various officials about flying saucers. He was told there was nothing to the subject, yet was simultaneously denied access to saucer-related documents.

Keyhoe's article "Flying Saucers Are Real" appeared in the January, 1950 issue of True (published December 26, 1949) and caused a sensation. Though such figures are always difficult to verify, Captain , Edward J. Ruppelt, the first head of Project Blue Book, reported that "It is rumored among magazine publishers that Don Keyhoe's article in True was one of the most widely read and widely discussed magazine articles in history."

Capitalizing on the interest, Keyhoe expanded the article into a book, The Flying Saucers Are Real (1950); it sold over half a million copies in paperback. He argued that the Air Force knew that flying saucers were extraterrestrial, but downplayed the reports to avoid public panic. In Keyhoe's view, the aliens ... wherever their origins or intentions ... did not seem hostile, and had likely been surveilling the earth for two hundred years or more, though Keyhoe wrote that their "observation suddenly increased in 1947, following the series of A-bomb explosions in 1945." Dr. Michael D. Swords characterized the book as "a rather sensational but accurate account of the matter." (Swords, p. 100)

Keyhoe wrote several more books about UFOs. Flying Saucers From Outer Space (1953) is perhaps the most impressive, being largely based on interviews and official reports vetted by the Air Force. The book included a blurb by Albert M. Chop, the Air Force's press secretary in the Pentagon, who characterized Keyhoe as a "responsible, accurate reporter" and further expressed guarded approval for Keyhoe's arguments in favor of the extraterrestrial hypothesis. Such endorsements only cemented the belief, held by some observers, that the Air Force's mixed messages about UFOs were due to a cover up.

Carl Jung argued that Keyhoe's first two books were "based on official material and studiously avoid the wild speculations, naivete or prejudice of other [UFO] publications."

Others have disagreed with Keyhoe's assessments. In his 1956 book, Edward J. Ruppelt wrote, "the Air Force wasn't trying to cover up", and declared that "The problem was tackled with organized confusion".

Ruppelt's book indicates that Ruppelt held some dim views of Keyhoe and his early writings; Ruppelt noted that while Keyhoe generally had his facts straight, his interpretation of the facts was another question entirely. He thought Keyhoe often sensationalized material and accused Keyhoe of "mind reading" what he and other officers were thinking. Yet Keyhoe cites conversations with Ruppelt in later books, suggesting that Ruppelt may have occasionally advised Keyhoe.

In 1956, Keyhoe cofounded the National Investigations Committee On Aerial Phenomena (NICAP). He was one of several prominent professional, military or scientific figures on the board of directors, which lent the group a degree of legitimacy many of the other contemporary "flying saucer clubs" sorely lacked.

NICAP founder Thomas Townsend Brown was ousted as director in early 1957 after facing repeated charges of financial ineptitude. Keyhoe replaced him; he was only slightly better at managing NICAP's finances, and the group continued their efforts

With Keyhoe in the lead, NICAP pressed hard for Congressional hearings and investigation into UFOs. They scored some attention from the mass media, and the general public (NICAP's membership peaked at about 15,000 during the early and mid 1960s) but only very limited interest from government officials.

However, there was increasing criticism of the Air Force's Project Blue Book. Following a widely publicized wave of UFO reports in 1966, NICAP was among the chorus which called for an independent scientific investigation of UFOs. The Condon Committee was formed with this goal in mind, though it quickly became emmired in infighting and, later, controversy. Keyhoe publicized the so-called "Trick Memo", an embarrassing memorandum written by a Condon Committee coordinator which seemed to suggest that the ostensibly objective and neutral Committee had determined to pursue a debunking operation well before even beginning their studies.

On 22 January 1958 Keyhoe appeared on a CBS live television show the Armstrong Circle Theatre to speak on the topic of UFOs. Keyhoe charged that a U.S. Congressional committee was evaluating evidence that "will absolutely prove that the UFOs are machines under intelligent control". However CBS stopped the audio portion of the live broadcast. Herbert A. Carlborg, CBS Director of Editing stated "this program had been carefully cleared for security reasons". HeraldTribune.com - De Void - The mainstream media's lonely UFO web log. - HeraldTribune.com

On 8 March 1958 Keyhoe appeared on The Mike Wallace Interview on ABC and spoke about flying saucers, contactees and the details of the Armstrong Circle Theatre censorship, which he blamed on the Air Force rather than CBS.

NICAP's membership plummeted in the late 1960s, and Keyhoe faced charges of incompetence and authoritarianism. By 1969 Keyhoe turned his focus away from the military and focused on the CIA as the source of the UFO cover up. NICAP's board, headed by Colonel Joseph Bryan III, forced Keyhoe to retire as NICAP chief. Under Bryan's leadership, the NICAP disbanded its local and state affiliate groups, and by 1973 it had been completely closed.

In 1973, Keyhoe wrote his final book about UFO's, Aliens from Space. It promoted "Operation Lure", a plan to entice extraterrestrials to land on Earth, and described the problems Keyhoe had getting information from government agents.

Beyond this book, Keyhoe had little contact with ufology as he settled into retirement. He did, however, speak at a few UFO conferences after his ouster from NICAP. In 1981 he joined MUFON's board of directors, but his membership was essentially in name only due to declining health, and he had little to do with the organization. He died in 1988 at the age of 91. He was buried in Green Hill Cemetery in Luray, Virginia.

Several of Keyhoe's books are now in the public domain and are available online.