Earthquakes ripple through New Orleans in the wake of a fracking operation, unsettling the city and setting a dangerous, unpredictable stage for everything that follows. Charlie [Edward Furlong] takes over as bus driver for a sick colleague, and he ends up behind the wheel of a bus filled with cheerful young riders, while his wife Katelynn [Tracey Gold], and their children Justin [Skyy Moore] and Annabel [Megan Adelle] set off on a separate bus tour around town. On the first bus, they meet Paul [Bug Hall], whose family—sister Petra [Olivia Hardt] and father Roy [Ethan Phillips]—runs a swamp-side boating business, adding an extra layer of practical knowledge to the group as the city descends into chaos.
Among the other travelers are Ernie and Tina [Tiara Ashleigh], along with an older man the group nicknames “Gramps” [Grant James]. The mood lightens only briefly before a frightening encounter with giant, albino spiders shifts the trip from sightseeing to survival. A stop at a drug store for bug spray ends in catastrophe as more spiders overruns the shop, claiming Gramps and a clerk, and forcing the survivors back to the buses.
Roy and Petra work a marina, already aware that something has gone terribly wrong. When Ernie is abducted by a spider, the surviving party flees aboard Roy’s boat, but the vessel crashes in a nearby forest. Tina is thrown overboard during the crash and is dragged away by another spider, while the rest make a desperate dash into the woods. Charlie’s bus comes under attack as well, and is wrecked against a tree, yet the passengers manage to stay safe inside as the spiders weave a thick web around the vehicle—until soldiers arrive, kill the spiders, and rescue the group.
As the immediate danger unfolds, Paul and his fellow travelers cross paths with locals Jean Jacques [Dane Rhodes], Roux [Earl Maddox], and Guillaume [Ned Yousef], who help lead the newcomers to a warehouse where they can regroup. There, Katelynn, a biologist, proposes capturing a spider so she can study it up-close. The attempt yields a startling discovery: the spiders are prehistoric in origin and act as a hive mind. Crucially, Katelynn explains that if they can locate and destroy the queen, the entire colony will die.
The warehouse soon comes under spider attack, forcing the survivors to flee into the woods. In the ensuing chaos, Roux [Earl Maddox], Guillaume [Ned Yousef], and Roy fall, while Katelynn and Petra are taken by the web-wielding swarm. Justin and Jean are evacuated by helicopter to safety, while Paul and Annabel press on to find a way to end the threat. They delve into a nearby cave to search for a nest, where they manage to rescue Katelynn and Petra from sticky imprisonment.
The queen spider finally emerges, driving the group back toward the water. They reach a boat and launch it, hoping to escape. On land, Justin and Jean reach a rooftop where Charlie has rejoined his son, and the drama continues to unfold as the queen relentlessly hunts them.
On the river, Katelynn begins to suffer an asthma attack, heightening the urgency. Paul commits to a perilous plan: kill the queen himself. He suits up in a diving outfit and dives into the city’s chaotic streets, where the queen is rampaging. Annabel and Petra find an ambulance to rush Katelynn to the hospital, while Charlie, Annabel, and Justin reunite on the rooftop with Jean, who briefly helps Paul before danger closes in. The queen captures Jean and Paul, creating a massive web that stretches between two buildings.
In a heartbreaking struggle, Jean is killed, and Paul is swallowed whole by the queen. Desperate but determined, he jams a piece of dynamite inside the creature, ties a rope to himself, and falls from the queen’s mouth. The spark travels along the rope to the dynamite and the queen detonates from the inside, taking the monstrous threat with it. Rescue troops arrive to pull Paul to safety, and Petra is reunited with the surviving group as the remaining spiders die off, bringing a fragile, hard-earned calm back to the city.