The game is set in 1969, 10 years after the original. The game begins with a KGB slide show meeting showing that Cryptosporidium-137 is now deceased. His clone, Cryptosporidium-138 (Crypto for short), made of pure Furon DNA, has taken his place and continuing to pose as the President of the United State. KGB intelligence also reveals that Crypto-138 is the first and only Furon to have genitalia, referred to only as "The Package". Seeing the Furons as a threat to the Soviet Union, the KGB destroy the Furon Mothership with a nuclear missile, killing Orthopox-13.
At a youth convention in Bay City, Crypto is held at gunpoint by a KGB agent. Seconds later, Crypto is attacked by a swarm of agents. He manages to hold off the agents and make it into Hashbury, where he encounters Pox's Holopox unit. Pox reveals that he managed to download a copy of his consciousness into the unit seconds before he was killed. Crypto, seeking revenge for the destruction of the Mothership, decides to shift his main mission on Earth to destroying the KGB. Using intelligence around Bay City, Crypto discovers that the KGB, under the control of Ivan Oranchov, are planning to convert Bay City into a communist farm using Revelade, a new health drink promoted by hippie guru Coyote Bongwater. Crypto defeats Bongwater and manages to prevent Revelade from being dispersed, only to discover that the KGB have a new plan to destroy Bay City using nuclear bombs. Using his Saucer, Crypto dumps the bombs into the bay before attacking the KGB base on The Rock, a prison island in the bay of the city. After destroying the base, Pox discovers that Oranchov has fled to Albion, England to work on the KGB presence there, managing to derail their mission in the USA.
In Albion, Crypto manages to kill Ivan Oranchov, who mutates using a type of spore. Here, Crypto teams up with Reginald Ponsonby-Smythe, the head agent of M16, and a rogue KGB agent named Natalya Ivanova. They discover that the spores have the power to mutate humans into monsters, which the KGB attempt to do in Albion, only to backfire when Crypto destroys the spore canisters being concealed at art exhibitions. Eventually, Ponsonby betrays Crypto, revealing he is the leader of the British branch of Majestic, and that M16 is actually Majestic Command, Sixteen Sector. After killing Ponsonby and puzzling over his cryptic reference that the Furons may not be the only aliens on Earth, he meets up with Natalya. The two quickly infiltrate the Soviet Embassy to gain information on Project Solaris, the KGB's confidential plans. Natalya discovers that they have set up affairs in Takoshima, an island in Asia.
Arriving in Takoshima, Crypto manages to steal confidential info on Project Solaris of the KGB in Takoshima City, where they discover that they have set up their base in an offshore location. Crypto meets the White Ninjas, a clan of ninjas who worship the Furons, where he needs to find Dr. Go!. Dr. Go! has information on the project, but is being held by the Black Ninjas and KGB. After doing some errands for him, Go! provides access to the KGB base hidden in the island's volcano. Inside, Crypto and Natalya are addressed by the mastermind behind the spore plot - Premier of the Soviet Union Milenkov. Milenkov shows a film clip of his men using spores on a Takoshimese intern called Kojira, who transforms into a giant Kaiju-like creature. Pox, unable to discover the science behind the mutation, suggests that Crypto traces the monster's movement towards the island. Kojira lands on the beach of Takoshima, leading to a giant war between the monster, Crypto, and the Takoshimese self-defense forces. After defeating Kojira, Crypto follows Natalya to Tunguska, the home of Project Solaris.
In Tunguska, Crypto helps Natalya break into the KGB base to gain more information, where she discovers that they are sending a shipment of uranium to a base in the north, which is covered in smog. Crypto helps Natalya's ally, Sergei, steal the shipment of uranium to the base. Pox and Crypto use the uranium to destroy alien-like generators below the base, removing the gas from the area. They reach the base, where they are surrounded by a large alien race. Pox quickly discovers that these aliens are the Blisk, the enemy that the Furons had thought they wiped out during the Martian War. Pox realizes that the Tunguska event of 1908 was actually a downed Blisk warship crash-landing into the Tunguskan hillside, not an atomic blast. After destroying the crashed Blisk warship and rescuing Natalya from a Blisk gas bubble, Crypto meets Milenkov face to face. Milenkov then retreats to his moon base, Solaris, in a Blisk shuttle.
Natalya and Crypto quickly follow him to the moon. Pox is unable to track Milenkov, but detects a load of Blisk. Even worse, Natalya has discovered that Project Solaris is actually a Blisk superweapon designed to bombard the Earth with Blisk spores and radiation, wiping out humanity and granting the Blisk control of Earth as their new irradiated, water-logged homeworld. They also discover the USSR have sent cosmonauts into space as slaves for the Blisk. Crypto disguises himself as a head scientist on the moon, and convinces the rest of the humans to go to war with the Blisk. Crypto manages to sabotage the weapon's firing mechanism. Upon doing so, Milenkov confronts Crypto. He then reveals that ever since the Blisk crashed, they have been controlling the Russian government after kicking off the October Revolution of 1917. He also reveals that every Premier before him and Leon Trotsky had been a Blisk, and they were responsible for several world crises, including the Cold War. After their conversation, Milenkov leaves. Crypto and Natalya battle for their various species to save the Earth by attacking and successfully destroying the Blisk hive with the O.M.G.W.T.F. Virus Pox developed in his lab. Natalya and Crypto escape from the destroyed hive, celebrating the defeat of the Blisk. However, Milenkov then shoots Natalya in the back the moment she was going to kiss Crypto, and then he reveals his true form - a heavily-armored Blisk.
After defeating Milenkov, Crypto relaxes in his Saucer while Pox appears on the video monitor, congratulating Crypto and eagerly anticipating his newly-cloned body. He has detected activity in the emergency cloning lab. He questions Crypto about it, then realizes that Crypto has cloned Natalya, and is extremely infuriated by this and begins yelling at him, just before Crypto abruptly shuts off the video monitor mid-sentence. Lying next to him, Natalya awakens briefly and favors Crypto with a smile and an invitation to wake her "in time for re-entry." As the game ends, Crypto leers at the player and admits to having made "a few adjustments," and sips on a martini.
- J. Grant Albrecht - Cryptosporidium-138
- Richard Steven Horvitz - Orthopox 13, The Freak
- Courtenay Taylor - Natalya Ivanova, Prudence Kane
- Jim Ward - Milenkov, Arkvoodle, Algernon
- Richard Tatum - Coyote Bongwater, Shama Llama
- Fred Tatasciore and Jim Meskimen - KGB Agents
- Anthony Head - Reginald Ponsonby-Smythe
Crypto can now body snatch humans, using them as a disguise. In addition, new weapons are unlocked by finding datacores ejected from the mothership before it was destroyed.
New Saucer landing points are unlocked by completing the challenges of the ancient Furon god Arkvoodle. The player is now able to call the Saucer from an empty landing site in order to eliminate back tracking, and it can now cloak for limited periods of time. In addition, the Abducto Beam actually abducts humans into the Saucer for usage in the Gene Blender, which upgrades Crypto's abilities.
Destroy All Humans! 2 has a co-op multiplayer mode, so the player can play through the story mode, free roam together and minigames, such as PK Tennis and Duel, with a friend.
The new "Free Love" feature enables Crypto to momentarily force his victims to groove to psychedelic music, thus making them forget they saw him. The new ability called "Mind Flash" mentally stuns everyone in the world for a brief period of time. The Jetpack has a longer lasting battery.