Plot

After witnessing gangster Eddie Kim (Byron Lawson) brutally beat U.S. Prosecutor Daniel Hayes (Scott Nicholson) to death in Hawaii, Sean Jones (Nathan Phillips) is escorted by FBI agents Neville Flynn (Samuel L. Jackson) and John Sanders (Mark Houghton) on a Boeing 747-400 to testify at the trial in Los Angeles.

Despite increased security for the flight, Kim arranges for a time-release crate full of venomous and constricting snakes to be placed in the cargo hold, in an attempt to bring down the plane before it reaches Los Angeles. To ensure the snakes attack the passengers, he has one of his henchmen, disguised as an airport ground employee, spray the passengers' leis with a special pheromone, which will cause the snakes to aggressively attack without being provoked. The pheromone is also further spread throughout the plane in the air circulation system.

The crate pops open midway through the flight and the snakes start making their way into various areas of the plane. A cat in the cargo bay, a young couple looking to join the Mile High Club, having sex in the lavatory, and a man using the bathroom, are the first killed. One of the snakes causes a short in the plane's electronics, so the plane's captain, Sam McKeon (Tom Butler) investigates by climbing down into the hold underneath the cockpit and resets the breakers. Before he can climb back up the ladder, he is struck and killed by a viper.

Co-pilot Rick (David Koechner) is alerted that the captain is down by Flight Attendant Claire Miller (Julianna Margulies). Rick believes the captain has suffered a heart attack. The stewardess goes to get Flynn and Sanders, who help move the captain's body.

Later, some coral snakes enter the cockpit and Rick uses his clipboard to hit them, accidentally releasing the oxygen masks throughout the plane. The snakes are then able to enter the cabin through the holes where the oxygen masks had been and they begin wreaking havoc among the passengers.

Numerous passengers, including Agent Sanders, are killed. Agent Flynn enters the cabin and uses a stun gun to ward off the snakes as he makes his way back. He realizes he has to turn around, as there are too many snakes and too much confusion among the passengers, so he yells to the passengers to make their way to the front of the plane.

Those who are able to get to the front of the plane follow the instructions of Flynn and begin putting up a blockade of luggage. The one male and two female flight attendants are doing their best to help the passengers. One stewardess, Grace Lin Shaye, rescues a woman's baby but in the process is fatally bitten.

Two little boys, sons of a Navy captain stationed in Hawaii, are traveling to Los Angeles alone. The youngest boy is bitten on the wrist and his wrist and hand swell dramatically. A young Latina woman -- the mother of the baby saved by Grace -- incises the swollen area and sucks some of the poison out.

Agent Flynn contacts FBI Special Agent Hank Harris (Bobby Cannavale), on the ground, who orders his men to find him the nearest snake expert. Ophiologist, Dr. Steven Price (Todd Louiso), who gets on a phone and speaks directly with Flynn. Price tells Flynn that something must be provoking the snakes for them to be acting so aggressively. After thinking about it, Price suspects a pheromone may be responsible.

Flynn tells Price that he will gather as many of the dead snakes as possible, so descriptions can be provided to Dr. Price and anti-venoms readied. First, he has to quell a potential insurrection by the passengers, who blame him and Jones for putting them in such a predicament. When he and the flight crew are able to calm the passengers to a degree, one of the passengers suggests they take pictures of the dead snakes to send to Price.

As some of the passengers start gathering dead snakes, a large snake in the cockpit attacks and temporarily disables the co-pilot. The plane starts to dip downwards, causing a food trolley to crash through the luggage blockade. The passengers flee to the upstairs first class cabin, exceeding the capacity of the stair railing and causing it to collapse. A huge boa constrictor simultaneously crashes through the overhead and falls into the aisle.

An obnoxious and rude passenger grabs a woman's small dog and throws it to the snake. The dog's owner is furious and starts hitting the man, but she falls back when the constrictor takes the man into it's coils and begins crushing him to death.

The passengers are able to get upstairs and block the stairwell with an inflatable life raft.

With pictures of the reptiles emailed to him, Price at first believes there will not be enough time to collect all the anti-venom that will be required. Price ultimately determines that a snake dealer living near Los Angeles was responsible for providing all those different snakes would likely have the antivenins necessary for all the species involved.

Music star Three G's (Flex Alexander) is traveling with two large bodyguards. Up to this point, he's been dealing as best he can with the snake situation, but begins freaking out, saying it's too hot and he can't breathe. He becomes aggressive and Flynn has to physically confront him. As they wrestle, Three G's grabs Flynn's gun. When Three G's is distracted by Troy (Kenan Thompson), one of the bodyguards, Flynn is able to get his gun back and orders Three G's back to his seat.

After Flight Attendant Claire Miller (Julianna Margulies) kills the snake in the cockpit with a fire ax, she and Flynn are able to mostly regain control of the jet. Rick then recovers consciousness and weakly retakes the controls.

The plane's interior starts getting too hot. Claire helps Flynn get down into the cargo hold to try and restore the air conditioning/ventilation system. He kills two snakes in the small elevator, then goes on down. Once inside the cargo hold, Flynn has to use a homemade flamethrower that Claire had made up for him to kill two more snakes. Finally, he's able to reset the power for the air conditioning.

One of Three G's bodyguards, Big Leroy (Keith Dallas), was bitten early in the attack, in the left butt cheek, so he has been suffering throughout.

The police find the snake dealer at his property in the desert. There's a quick gunfight and, as the dealer is trying to get away, he is bitten by one of his deadlier snakes. Special Agent Harris threatens to withhold the anti-venom that the dealer needs unless he provides information about the snakes on the plane. The dealer reveals that Kim hired him to obtain the snakes, most of them illegal to import into the United States. He also tells them that pheromones were sprayed on the flower leis so they would circulate throughout the plane's air conditioning system and stimulate the snakes to behave aggressively. The dealer then receives a dose of anti-venom and the rest of his supply of anti-venom is commandeered for the plane's victims.

Harris gives orders to have Eddie Kim arrested. Harris then contacts Flynn, telling him that anti-venom will be ready for the passengers when they land.

Flynn has to force the door to the cockpit open. Rick falls out dead and Flynn sees that there are multiple snakes inside the cockpit. He slams the door shut.

When Claire goes to the passengers and asks if anyone knows how to fly a plane, Three G's volunteers Troy. Troy looks at him like he's crazy, but after thinking about it, he acknowledges that he has over 2,000 hours experience and could do it.

Flynn says that he's had it with the snakes and decides he's going to get rid of them. All the passengers are told to tie themselves into their seats. When they are all ready, Flynn draws his pistol and shoots out two cabin windows, causing the plane to depressurize. He then flings open the cockpit door. All loose gear, including the snakes, are sucked from the plane.

Flynn helps Troy get into the cockpit, where he takes the controls. Troy is surprised at how familiar the controls appear to be. He brings the plane level at an altitude where the pressure is no longer working at extracting everything from inside the plane. When contact is made with air traffic control, Troy is asked if he has flight experience. Troy confirms that he's flown military aircraft of several types. It's soon evident that Troy is speaking about his experience with video game flight simulators.

Troy is the best option available, so the plane is his to land or crash. Troy bounces the plane hard a couple of times, but manages to bring it down. He needs a little harsh encouragement from Flynn to get the plane turned left and braked, but he gets that done too, with the jet coming to rest just short of a hangar.

The passengers deplane, via an emergency slide, as the emergency vehicles, Dr. Price, and the anti-venom arrive.

Just as Flynn and Sean are about to disembark, a remaining snake jumps out and bites Sean in the chest. Flynn draws his gun and shoots the snake, and Sean, knocking him out of the plane and down the chute. Police rush to Sean and lift him off the chute and check him out. The snake was killed but Sean is alive and unharmed, due to the fact that he was wearing a bulletproof vest.

Flynn offers to take Claire to dinner in return for her saving his life. She tells him to call her. The young flight attendant who was working first class, and took an immediate liking to Sean, writes her phone number on Sean's palm, so Sean and Flynn have their romantic bases covered in the near term.

Sean then reminds Flynn of the time they first met. It was on the balcony of his apartment, when some of Kim's henchmen were breaking in to kill him, and the first thing Flynn said to Sean was, "do exactly as I say and you'll live." So, now, Sean tells Flynn that he needs to do as he says. He is referring to surfing. Sean takes Flynn to Bali and teaches him how to surf. They'd discussed it on the plane, prior to the snakes attacking, and Flynn admitted that he'd tried surfing, but couldn't stay on his board. The story ends with Sean giving Flynn his first lesson.