In Destroy All Humans!, players assume the role of Cryptosporidium 137 (Crypto for short), a warrior and member of the Furon alien race. After centuries of warfare against inferior species using unchecked nuclear weaponry left their species impotent and without genitalia, the Furons were unable to sexually reproduce and became forced to turn to cloning as means of reproduction, as well as a process by which to achieve immortality. However, after generations of clones, the Furon DNA is degrading, and each clone is becoming less and less stable.
Fortunately for the Furons, a Furon scout ship came across Earth many millennia ago while returning from destroying the Martians. The Furon spacefarers eventually bred with the ancestors of the human race for an unknown reason, inserting a strand of Furon DNA into the human gene pool.
Because of this, it is revealed, each human contains a small amount of Furon DNA in their genetic code. Crypto is sent to Earth to harvest this DNA from human brain stems, locate and rescue his previous clone, Cryptosporidium-136 (referred to as his brother in the instruction manual), and spearhead a Furon invasion of Earth. The game is set up in a "sandbox" fashion. The player has a selection of weapons and mental abilities at their disposal, as well as access to Crypto's flying saucer. Destroy All Humans! implements the Havok physics engine, allowing for ragdoll effects on bodies and destructible environments.
The game starts with Crypto 136's capture by the U.S. Army. Some time later, Orthopox 13 and Crypto 137 travel to Earth, seemingly at first to rescue 136. Crypto arrives at Turnipseed Farm in the Midwest, where he at first mistakes cows for Earth's dominant life-form. The Majestic are alerted to the Furon presence when Crypto decimates an army brigade passing through the area. Orthopox then reveals to Crypto that their mission on Earth is to extract human brain stems, which contain Furon DNA given to them by Furon scouts eons ago, in order to save the genetically dwindling Furon race.
After several missions in the Midwestern town of Rockwell and the California suburb of Santa Modesta, Crypto and Orthopox become aware of Majestic, and begin crippling government attempts to stop them by performing acts such as destroying Area 42 with an atomic bomb and killing General Armquist. Throughout the game, Crypto's various acts are covered up by the government and media, which attribute them either to freak accidents or communism.
The game climaxes in Capitol City (essentially Washington DC), where Crypto assassinates President Huffman and massacres most of the US Congress in a scene similar to Mars Attacks!. Soon, the U.S. government seemingly surrenders to the Furons. Crypto meets Silhouette, leader of Majestic, in front of the Capitol. After a brief scuffle with Silhouette, Crypto discovers that 'he' is a woman. Silhouette unveils the Roboprez, which is a towering mech controlled by President Huffman's brain. Crypto defeats Roboprez in his flying saucer, and then defeats Silhouette in a firefight at the Octogon (the game's version of the Pentagon). As Silhouette dies, she reveals that there are other Majestic divisions all over the world. Crypto, however, is confident that without Silhouette's leadership, Majestic will be totally powerless to resist the Furon takeover.
The game ends with Huffman making a televised speech, assuring America that the recent events were the work of Communists, who have poisoned the US water supply, and that as a result testing centers have been set up all across the country to scan people for harmful toxins. People are then shown being herded by Army soldiers into strange machines, apparently for brain stem extraction. Huffman is then revealed to be Crypto in disguise.
Destroy All Humans! is set in the 1950s United States (the exact year is not specified throughout the game; 1954 and 1957 are implied to be the year in the first game, and the second game suggests 1958 or 1959) and consists of six settings. These include:
Nearly all buildings and structures in these environments can be destroyed, although humans can become alarmed by Crypto's presence at these locations. While some run or hide, others are armed and will fight back. An alert system, much like Grand Theft Auto's "wanted level", denotes how much attention Crypto has attracted, which can lead to police, military, and eventually a shadowy group called the Majestic joining the chase.
Military technology in the game is depicted as being far more advanced than it was in the real 1950s, with the US Army having possession of robots, sentry guns, automated anti-air batteries, Tesla coils, and mechs. The Majestic group also seems to be equipped with energy weapons, although it could be assumed that they are reverse-engineered Furon technology. They are also similar to the weaponry in Men In Black II, a video game based on the movie series of the same name.
The hub of the game is the Furon mothership in orbit around Earth, which greatly resembles the alien mothership from Close Encounters of the Third Kind. From there players can receive missions, upgrade weapons, and view unlocked content. This is also the portal to each of the game's Earth settings.
Coming from the planet Gorta in the Proxima Centauri system, the Furons are aliens that have a similar appearance to Greys (aside from their mouth of sharp teeth), are named after diseases, and are a highly advanced race who use their technology for science, but also for war. Because they are a warlike race, their weaponry is extremely deadly. It is revealed that use of unregulated atomic weaponry caused a fatal mutation in the Furon race, whereby they could no longer procreate, due to their complete and utter lack of genitalia. Using their advanced biotechnology, they began cloning themselves, rendering each Furon basically immortal, memories and personality somehow being transferred to each new clone. However, with each new clone, errors start to appear in the genetic material, leading to unpredictable results. Without an infusion of uncorrupted Furon DNA, they will clone themselves into extinction.
The Furons use a spherical device called the "HoloBob" to imitate the appearance of any nearby human. This allows a Furon to travel amongst humans unnoticed, or in two cases, take the appearance of a public figure to send out a message to humans. The HoloBob requires psy energy, called "Concentration" in the game, which can be continually replenished by reading the thoughts of unknowing humans or other animals. This disguise is not without flaw, as the Majestic have the uncanny ability to see through and destroy the disguise. Crypto will flash red when nearing a Majestic; if he comes too close, the disguise will vanish.
Upon release, Destroy All Humans! received mostly positive reviews, although some reviewers complained of repetitiveness in mission design and gameplay. Graphics were described in a generally good light, except for the large amount of pop-up in the game. Most praised was the game's satirical tone and comedic gameplay, highly derived from 1950s-era science fiction movies. With Crypto's mind-reading abilities an important feature of gameplay, much humor comes from the repressed thoughts these inhabitants of this supposedly-innocent period of American history hold, including their fantasies about taking Bettie Page and Rock Hudson over Doris Day, reactions to the findings of one "Dr. Kinsey", current and possible-future presidents, and of course, the Red Menace.
Those who pre-ordered Destroy All Humans! received either a soundtrack CD or a copy of the 1959 Edward D. Wood, Jr. sci-fi movie Plan 9 from Outer Space. The game contains many references to the movie, including actual scenes from the movie shown at a drive-in theater, and on the Mothership.
On October 26, 2005, THQ announced that Fox Broadcasting has purchased the rights to the game and is planning a computer-animated comedy, based on the game, to air in primetime. Jim Dauterive, previously of King of the Hill, will be a writer and executive producer of the TV version of Destroy All Humans! As of April 2008 nothing has been unveiled. The show is also referenced in Destroy All Humans! 2, in the Salad Days bonus video, in which Pox and Crypto reminisce on the past game, and talk about the possibilities of the game's future.