20 years have passed since the War of 1996. Sometime after the war, the United Nations founded the ESD, the Earth Space Defense, a global defense advanced research program that reverse-engineers alien technology used to defend Earth against extraterrestrial threats. Civilization has also been restored and the planet is united in world peace following humanity's victory against the alien threat, and major cities, including Washington, D.C., were rebuilt and modernized amalgamated technologies. After establishing Area 51 as its headquarters, the ESD has also set up bases on the Moon, Mars, and Rhea, a moon of Saturn, as well as orbital defense satellites around Earth, as fortifications to prepare for future invasions.
In the African state Republique Nationale d'Umbutu, ESD Director David Levinson meets with warlord Dikembe Umbutu and Dr. Catherine Marceaux before traveling to an alien saucer and discover that prior to their previous defeat, the aliens had been drilling into the planet and sending out a distress signal to their homeworld. It's also revealed that, following their personal encounters with the aliens, former U.S. President Thomas Whitmore, Dr. Brackish Okun, and Umbutu were among those telepathically linked to the aliens' collective consciousness, and are having visions of an unidentified spherical object.
The unidentified spherical ship from the visions soon appears from a wormhole near Earth's moon. Suspecting it to be an alien threat, the ship is shot down under orders from the Security Council despite protests from Levinson. Two American fighter pilots named Jake Morrison and Charlie Miller defy their orders and collect Levinson, Marceaux, Umbutu, and U.S. federal controller Floyd Rosenberg on a space tug and head for the wreckage in the Van de Graaff crater, recovering a large container. Then an alien mothership, responding to the distress call, appears and destroys much of Earth's defense systems before landing over the North Atlantic Ocean, where it begins to drill towards Earth's molten core for fuel as well as to destroy the planet. The group manages to escape in the space tug and return to Area 51.
In a prison facility in Area 51, Whitmore, Levinson, and U.S. General Joshua Adams' group interrogate one of the aliens held in captivity. It's revealed that the aliens exist in a hivemind and that there is a Queen that is spearheading the invasion. After having killed one of their Queens back in the previous war, Levinson theorizes that if they kill this new Queen, her forces will cease and lie dormant once again. Captain Dylan Hiller leads an ESD aerial fleet in a counterattack, but are quickly ambushed and overwhelmed once within the mothership, leaving Dylan, Jake, Charlie, and Rain Lao, a Chinese pilot, as the few survivors.
Back in Area 51, Okun breaks the container open and discovers a giant white sphere of virtual intelligence, releasing her. The sphere reveals that her mission is to evacuate survivors to a planet of refugees targeted by the aliens, whom she refers to as the "Harvesters", to unite them for an attack on the Harvesters' home planet. On the mothership, the surviving pilots manage to escape by hijacking several alien aircraft, and Dylan, Jake, Charlie, and Rain use them to pursue the Queen's ship, which is inbound for Area 51 to capture the sphere.
Knowing the Queen will be coming for the sphere now that she knows her location, the ESD hides her in an isolation chamber and use a decoy in the space tug to lure the Queen into a trap. Whitmore volunteers to pilot the ship in a suicide mission, succeeding in sacrifcing himself to destroy the Queen's ship by detonating a bomb. However, the Queen survives due to being armed with a force field, and she begins to attack on foot. During the battle, Whitmore's daughter, Patricia, manages to score a critical hit on the Queen, disabling her barrier, and the team succeeds in killing the Queen before she can take the sphere.
Following the Queen's demise, the alien fighters are rendered inactive, while the mothership ceases drilling and retreats back into space. Okun reveals that the sphere has asked humanity to lead her resistance and in exchange, offer them new technology to finally take the fight to the Harvesters' homeworld.
