The plot begins with an opening narration explaining that Earth was being observed by extraterrestrials with immense intelligence and no compassion. As man dominated the world without doubt, much like microorganisms swarming in a drop of water, these beings plotted to take it all from us.
Divorced longshoreman Ray Ferrier works as a crane operator at a dock in Brooklyn, New York, and is estranged from his children: 10-year-old daughter Rachel, and teenage son Robbie. Ray's pregnant former wife, Mary Ann, drops the two off at his house in Bayonne, New Jersey, on her way to visit her parents in Boston.
Later, a strange storm occurs during which lightning strikes multiple times into the middle of a local intersection, causing an EMP that disrupts all technology and electricity. Ray joins the crowd at the scene of the impacts, where a massive "tripod" war machine emerges from the ground and uses powerful energy weapons to destroy the area, disintegrating most of the witnesses into a grey dust. Ray collects his children, steals a van that had just been repaired, and drives to Mary Ann's empty home in suburban New Jersey to take refuge. That night, they take shelter in the basement, but they soon hear a strange roaring noise followed by an explosion, which destroys the house. The next morning, Ray discovers a Boeing 747 had crashed into the neighborhood wherein he meets a wandering news team surveying the wreckage and scavenging meals from it. The team explains to him there are multiple tripods that have attacked major cities around the world, adding that the tripods have force shields to protect them from human weapons, and the tripods' pilots traveled to Earth within the lightning storms as a way to enter their machines, which are assumed to have been buried underground for millions of years.
Ray decides to drive the kids to Boston to be with their mother, but a desperate mob swarms their vehicle, forcing them to abandon it. They eventually get to a Hudson River ferry only to be surrounded by tripods, which either massacre or abduct many of the refugees, but Ray's family manages to escape. They then witness U.S. Marines engaging in a futile battle with some tripods; Ray tries to stop Robbie from joining the fight, but is reluctantly forced to release him so he can take Rachel to safety. Ray and Rachel flee as the machines annihilate the marines, and are offered shelter in a farmhouse basement by a deranged man named Harlan Ogilvy.
The three remain undetected for several days, even as a probe and a group of the tripods' alien pilots explore the basement. They soon discover the aliens have started cultivating a red-colored vegetation across the landscape that is quickly spreading; the group deduces the aliens are modifying Earth to make it more like their home planet. The next morning, Ogilvy suffers a mental breakdown upon witnessing the tripods harvesting human blood and tissue to fertilize the alien vegetation. Fearing Ogilvy's mad shouting will alert the aliens, Ray reluctantly kills him. A second tripod probe catches the Ferriers sleeping; Rachel flees and is abducted by a nearby tripod, and Ray joins her after picking up a belt of grenades. With help from other abductees, Ray uses the grenades to destroy the tripod from within, freeing them all.
Ray and Rachel arrive in Boston, where they find the alien vegetation withering and the tripods inexplicably collapsing. When an active tripod appears, Ray notices birds landing on it, indicating that its shields are now offline. Ray successfully alerts the soldiers escorting the fleeing crowd, who shoot it down using anti-tank missiles. As the soldiers advance on the downed tripod, a hatch opens and a sickly alien struggles halfway out before dying. Ray and Rachel finally reach Mary Ann's parents' house, where they are reunited with Mary Ann and Robbie (who somehow managed to survive).
A closing narration explains the aliens' deaths was due to their immune systems being unable to handle the countless billions of microbes that inhabit the Earth, and that humanity has "earned" the right to the planet by virtue of naturally coexisting with the rest of its biosphere.
Tom Cruise as Ray Ferrier
Dakota Fanning as Rachel Ferrier
Justin Chatwin as Robbie Ferrier
Miranda Otto as Mary Ann Ferrier
Tim Robbins as Harlan Ogilvy
Rick Gonzalez as Vincent
Yul Vázquez as Julio
Lenny Venito as Manny the Mechanic
Lisa Ann Walter as Sheryl
Ann Robinson as Grandmother (she played the lead role of Sylvia van Buren in the 1953 film)
Gene Barry as Grandfather (he played lead role of Dr. Clayton Forrester in the 1953 film)
David Alan Basche as Tim
Roz Abrams as Herself
Camillia Sanes as News Producer
Amy Ryan as Neighbor with Toddler
Danny Hoch as Policeman
Morgan Freeman as the Narrator (voice)
Dee Bradley Baker as Alien Vocals (uncredited)
Columbus Short as Soldier
Channing Tatum as Boy in Church Scene (scene cut)