At an airport, a nervous passenger, George Phelps, goes to the restroom while he waits for his flight. Another man comes in and notices him trying to calm down, and tries to assure him about the odds of dying in a plane crash. George isn't reassured. As he washes his face, a black smoke-like substance flows in through the air conditioning grille and flows into the man's eyes.
Aboard the plane, Flight 2485, the stewardess, Amanda Walker, welcomes the passengers on board. When George enters, he confidently assures her that he plans to have a pleasant flight, and she notices that his eyes seem black. Amanda dismisses it as a trick of the light. Forty minutes into the flight, the man checks the time and then goes to one of the exits. As a teenager looks on, George opens the door and is sucked out as a passenger, Max Jaffe, looks on in horror. The door flies off and hits the rear tail wing, and the plane goes down.
Dean is sleeping in a motel room when Sam arrives with coffee at 5:45. Sam insists he's been sleeping okay, but Dean worries that if he's not resting, he'll endanger both of them. When he wonders if Sam is still having nightmares about Jess, his brother admits he's having nightmare about everything involving the job, and that's getting to him. Dean claims that it doesn't bother him any more but Sam isn't convinced. A friend of Dean's, Jerry Panowski, calls and notes that Dean and John helped him with a poltergeist a few years ago. Jerry has something worse to report, and asks if they can talk in person.
The brothers meet with Jerry, an airline inspection official, who says he needs their help again. He mentions to Sam that John used to talk to him all the time about how proud he was of Sam going to college. Dean lies and says that John is busy. Jerry plays back the cockpit recorder for them. As the plane goes down, they hear a growling noise on the recording. Jerry explains that the cause is being listed as mechanical failure, and only seven people survived. The pilot, Chuck Lambert, is one of the survivors and a good friend of Jerry's. Chuck is blaming himself, but Jerry doesn't believe it was his fault. He agrees to get the brothers the manifests, but warns that the wreckage is locked down in an evidence warehouse. Dean assures him they can get in.
One stop at a copy center later, Dean has fake Homeland Security ID for them. Sam has confirmed EMF on the recorder, showing the presence of supernatural energies. When he clears up the recording, they hear the mysterious voice say, "No survivors." Sam notes that there is a long history of phantom travelers on planes and ships, including Flight 401. He suggests they talk to Max Jaffe, a local who is in a psychiatric hospital. He initially denies seeing anything unusual, but Dean notes that he checked himself into the hospital. When he pushes Max, the man admits that he was delusional. Sam convinces him to tell them that he saw George and he had black eyes. Max notes that he checked and it would have been impossible for a human being to open the door against the pressure. He confirms that the passenger was an actual person, not a ghost, much to Sam's surprise.
Next, the brothers go to George's house and talk to his wife, Bonnie. She explains that her husband was going to a convention in Denver and was scared of flying. Bonnie never noticed anything strange about George. Dean figures they'd better go to the warehouse next. They buy suits and go to the government warehouse, flashing their badges to get past the security guard. Dean uses a homemade EMF meter to scan for supernatural energies and find it on the emergency door handle. Sam takes a sample Outside, two real Homeland Security agents arrive and the security guard notes that two agents just went in. The brothers get out just in time and avoid capture.
Chuck meets with a flight instructor, Lou, to go on a small-plane testing flight. As a nervous Chuck waits in the lounge, the black cloud emerges from an air vent and flows into Chuck.
Sam and Dean have Jerry analyze the sample and he confirms that it's sulphur. The brothers figure that it's demonic possession on a larger scale than they've ever heard before.
A now confident Chuck lifts on in the small plane and confirms they've been up forty minutes. He then knocks out Lou and takes the plane down. On a country road, a farmer watches as the plane crashes nearby.
At the motel, Sam goes over legends of demonic possession. According to Japanese legend, demons are responsible for disasters. Dean figures that they're dealing with a modern demon who has figured out a way to up the body count. He wonders if they're up to handling something so big, and they both admit that they wish John was there. Jerry calls to inform Dean that Chuck crashed the plane, killing himself and Lou. They go to the crash site and get samples, and have Jerry confirm that it's sulphur. Sam notes that both crashes occurred at the 40-minute mark, and that the number is symbolic of death. There have been six crashes in the last decade that occurred in the 40-minute mark, and no survivors until Flight 2485. They figure the demon is going after the survivors to finish the job.
En route, Sam confirms that the flight attendant, Amanda, is the only one with any plans to fly. She's going back on the job that night, and they have five hours to get there. She's turned her cell phone off and Dean vows to get there. They arrive with 30 minutes to spare, and Dean calls Amanda claiming to be a doctor. He tells her that her sister Karen was in an accident, but Amanda just talked to her. She realizes something is going on and figures it's a prank by her boyfriend's pals. Dean plays along but isn't able to convince her to wait. As Amanda goes on the plane, the black demonic essence flows out of a nearby vent.
Sam realizes that they have no choice but to get on the plane and exorcise the demon. Dean admits he's afraid of flying and Sam suggests he go by himself, but Dean insists on accompanying him. They board the plane and Dean tries to avoid panicking. Sam tries to get him to focus and warns that they have 32 minutes to find the demon and perform the exorcism. They figure it's someone with an addiction or emotional distress, and suspect Amanda. Dean goes to talk to her and plans to say the Latin name of God to see if the demon flinches. He makes small talk with her and she admits she's a bit nervous, but is clearly confident. When he says the Latin name of God, "Cristo," she doesn't respond despite repeatedly attempts. He goes back to his seat and tells Sam that Amanda is clean and unlikely to be possessed. When they hit turbulence, Sam manages to calm his brother down and then informs Dean that he's found the proper exorcism ritual. The first part causes the demon to manifest, making it more powerful. The second part sends it back to Hell. Now they have to find it.
Dean scans the passengers for EMF activity without success. With time running out, they pass near the cockpit and the EMF meter goes wild as the co-pilot emerges. Dean says "Cristo," causing the demon to briefly manifest its black eyes. With 12 minutes remaining, the brothers try to convince Amanda of what's happening. She doesn't believe them at first, but they note that Chuck died recently in another plane crash. She finally tells them that she saw George's black eyes, and they ask her to convince the co-pilot to come back so they can conduct the exorcism. She reluctantly agrees and lures the possessed co-pilot back. When he arrives, Dean knocks him down, gags him, and burns him with holy water as Amanda stares on in shock. Sam asks her to keep everyone out and she agrees, As they conduct the ritual, the demon pulls the gag off and tells Sam that Jess is burning in Hell. Sam completes the first part of the ritual, but the demon manages to kick the book down the hallway. The black cloud flows into the vents and the plane starts to go down. Sam finds the ritual book and performs the second half of the ritual. Lightning strikes the plane and the demon is sent back to Hell.
Later, the airplane lands and the FAA interrogates the co-pilot, who doesn't remember anything. As Amanda gives her statement, she mouths "Thank you" to the brothers. As they slip away, Sam points out that the demon knew about Jessica. Dean tries to reassure him, pointing out that demons can read minds, and that they lie. Later, they meet with Jerry, who thanks them for what they did. He tells Sam that John will be proud of him. As they go, Jerry explains that John gave him Dean's cell phone. When he called John, he got a voice message saying to call Dean.
Later, Dean calls John's number, while Sam notes that it's been out of service for months. They listen to John's message, which tells anyone calling to ask Dean for help.