The film starts off with a man, Michael, (Jenkins) waking up alone, seated in a chair in a grungy, sealed room. A device is secured around his neck. A nearby TV turns on, showing the familiar "clown" figure Billy the Puppet Jigsaw (Bell) employed in the first film. Jigsaw's recorded message tells the man that as punishment for being a police informant, spying upon and betraying others, and for not appreciating life, he has to play Jigsaw's "game". When the timer goes off, the device will snap closed, impaling his head with multiple sharp nails lining the inside of the device (similar to an iron maiden). The TV cuts to the man lying on an operating table with a shadowy figure standing over him, as Jigsaw tells him (and an x-ray photo confirms) that the key to unlock the device has been implanted behind his eye. A scalpel has been left for the man to carve the key out from his eye socket, if he chooses to do so. As he gets up from the chair, he triggers a timer built into the device. The terrified man fails to extract the key in time and is killed.
Detective Matthews (Wahlberg) is called to the scene, as the deceased was his informant, and discovers a message scrawled on the ceiling which reads, "Look Closer, Detective Matthews." Matthews spots an engraving on the metal contraption, and believes he knows where Jigsaw is ??? the Wilson Steel building. After his initial reluctance, his former partner, Kerry (Meyer), finally convinces him to join the team entering the building to arrest Jigsaw.
After some of the accompanying S.W.A.T. team fall prey to one of Jigsaw's booby traps, they find Jigsaw. Very ill due to his advanced stage cancer, he offers no further resistance as the SWAT team handcuffs him. As they start to take him away, he directs Matthews and the others to an adjoining room, which contains several monitors showing various rooms of a house, along with an electronic timer counting down from two hours. On one of the monitors, Matthews sees a room with eight people forced to play Jigsaw's latest game; among them is Matthews' own son, Daniel. He later notices that all other seven are people he has framed for crimes they did not commit.
The story switches to the captives in the house. Amanda (Smith), a survivor from the original film, breaks through a loose section of a brick wall in the room they found themselves in, and finds a key and a tape recorder containing a taped message from Jigsaw explaining their predicament: they have been exposed to a deadly toxic nerve gas (specifically sarin, which Jigsaw references as having been used in the real-life gas attack on the Tokyo Subway) and will die within two hours unless they find the antidotes that are hidden around the house (they are given the clue that they all have the combination to the safe in the "back of their mind", and that the combination can be found "over the rainbow"). The key has a note warning them not to use it to open the door in the room, but Xavier (Franky G) ignores the message and turns the key in the lock while Gus (Nappo) looks through the eyehole. The lock is rigged to fire a gun pointing directly at the eyehole. The gun fires into Gus' eye, killing him. Amanda reveals to the others that she has had to play one of Jigsaw's games before, and pleads with them that they have to follow his "rules".
Xavier (Franky G) and Addison (Emmanuelle Vaugier) confront Obi (Burd) for putting them thereThe terrified captives begin to explore the house. Laura (Mitchell) finds another door leading to the basement, with another tape marked for Obi (Burd) which reveals how he had assisted Jigsaw to get the others in the house, and explains that there are two antidote syringes inside a large furnace in the room. He tells Obi that, though he may have one syringe for himself, the other is his to donate, but will come at a price. Obi climbs inside to retrieve the syringes, grabs the first, but the second causes the door to close and the furnace to ignite. Obi is burned to death before the other captives can get him out, and both antidotes are lost.
Meanwhile, Jigsaw insists that Matthews has to play a game to save his son. The game is simple, he just has to sit with Jigsaw ??? by himself ??? and listen to what he has to say. All the while, the timer is ticking away in the room with the monitors. Matthews is reluctant to listen to Jigsaw, but Kerry insists that Matthews should "humour" Jigsaw. Through a series of flashbacks, Jigsaw is revealed to be a terminal cancer patient (and, apparently, was given this news by Dr. Lawrence Gordon from the first film), who attempted suicide by driving his car off a cliff. However, Jigsaw survived the suicide attempt, despite severe injuries. Henceforth, Jigsaw resolved to test the human ability to overcome great suffering in order to save their life.
In the house, after forcing open a door into another room, the captives find another tape marked for Xavier. On the tape, Jigsaw condemns him for his life as a drug trafficer and states that if he wants to escape, he must "wallow in the filth that he made others wallow in". Daniel pulls back a sheet to reveal a pit full of syringes. The message says that a key is in the pit which will open a door concealing another antidote; the door, however, is rigged to a timed lock that will close permanently in a short time. Xavier takes hold of Amanda and throws her into the pit, shouting at her to dig through them to find the key. Screaming in the pain brought on by being pierced with dozens of needles, Amanda finally finds the key and gives it to Xavier. He races to the lock, but fumbles and drops it. The door's timer expires, sealing the door forever. Daniel (Knudsen) helps Amanda out of the pit.
Meanwhile, after having grown tired of listening to Jigsaw and helplessly watching one captive after another die while the timer runs down, Matthews finally snaps and unleashes his rage on the old man. Savagely beaten and battered by Matthews, Jigsaw utters his "Game over" catchphrase and finally agrees to take Matthews to the house, on the sole condition that they travel alone.
In the house, Xavier goes insane and begins to try to kill his fellow captives to retrieve the different colored numbers written on the back of their necks (the answer to Jigsaw's cryptic clue "You all possess the combination. It's in the back of all your minds."), armed with a spiked baseball bat found earlier in the film. The different colors, representing the colors of the rainbow, will reveal the combination of the safe when put in order. This combination (supposedly) unlocks the safe that was found in the first room. He kills Jonas (Plummer), retrieves his number and color, and proceeds to go after the others.
Meanwhile, in the corridor, Laura (Mitchell) points out the answer to another cryptic clue given earlier by Jigsaw ("X marks the spot), before succumbing to the nerve gas. Addison (Vaugier) examines the photo frame and finds a photo of Daniel and Matthews together, marked "Father and son". The clue was placed by Jigsaw to incite hatred in the other captors because Daniel is the son of the police officer who framed them. Amanda finds Jonas' body and realizes that Xavier wants to kill the other captors and goes back to rescue Daniel.
While pursuing Amanda and Daniel, Xavier comes across Addison who has fallen victim to another of Jigsaw's contraptions ??? a glass box suspended from the ceiling that contains an antidote. On the underside of the box are two holes just wide enough to put an arm through each, once pushed past the blades covering them. She discovers too late that the blades are arranged similar to a Chinese finger trap, preventing her from removing her arms once inside; the metal edges dig deeper into her flesh the harder she pulls. Xavier reads her number and leaves her to die in the contraption.
Meanwhile, without telling his team, Matthews leaves with Jigsaw in his van. However, shortly afterwards, the police finally locate the broadcast location of the video feed of the captors and leave quickly to save them. Jigsaw directs Matthews to the house in which the events have taken place, and gives Matthews the key to get inside. Matthews gets inside and finds the dead bodies of the victims littered throughout the rooms.
Elsewhere, Amanda and Daniel retreat to the room where all the captives awoke, as Xavier attempts to break through the door to get at them. Amanda pushes aside the safe, revealing a trap door underneath. They go through the hatch just as Xavier breaks through. He follows them, cornering them in the infamous bathroom from the first movie. The bodies of Adam and Zep, and Dr. Lawrence Gordon's severed foot are still there, in a state of advanced decay and covered with fungus and mold. Daniel slumps against the wall, aparrently dead. Amanda tells Xavier that, as Daniel has died, she remains the only person capable of reading his number, and that if he kills her, he won't be able to find out the number on his own neck. Xavier, now completely insane from the nerve gas, takes his knife and slices a section of skin off the back of his neck so he can read his own number. As he moves in to kill Amanda, Daniel jumps forward, crushing Xavier's ankle and slits Xavier's throat using the hacksaw from the first movie, killing him.
While the S.W.A.T. team enters what they and Kerry assume to be the same house, Kerry watches the monitors, confused that the cameras aren't showing them in the house. As the SWAT team investigate it is revealed that the images on the monitors in Jigsaw's hiding place were not a live feed, but were showing a recording of earlier events, and that the broadcast location where the S.W.A.T. team has arrived is not the location where the events have taken place. Jigsaw was, therefore, speaking cryptically when he said that "I haven't looked at the monitors for some time, so it'd be hard for to say, but I would imagine that, um, Daniel's cowering in a corner with a look on his face...".
Meanwhile, Detective Matthews enters through a back door, finds the open trapdoor and goes down to search for Daniel. A shot of a syringe here explains how Daniel has survived the exposure to the nerve gas. Matthews gets into the darkened bathroom, and sees someone lying in the bathtub. He approaches cautiously, but the person inside, wearing the same animal mask from the first film, leaps up and stabs him in the leg with a syringe. Matthews drops to the floor. The attacker later removes the mask, revealing herself to be Amanda.
The timer in the room at Wilson Steel expires and a safe across the room opens to reveal Daniel, wearing an oxygen mask, weary but alive. He had been there when the S.W.A.T. team came into the building and found Jigsaw two hours earlier; had Matthews followed the rules to Jigsaw's "game", he would have found his son "in a safe, secure place" just as Jigsaw had told him.
When Matthews wakes up, he finds an audio cassette player lying next to him. Playing the tape, he learns that Amanda has become Jigsaw's prot?©g?© and has now taken his place. In a series of flashbacks it is revealed why Jigsaw was happy to sit back while Matthews destroyed his work, and that Amanda was the one who brought Daniel back to be placed in the safe quoting that Jigsaw said that Matthews' son was in a "safe place." Matthews then watches helplessly as Amanda closes the door on him. "Game over," she says, repeating Jigsaw's catchphrase. Matthews, chained to a pipe, is left in the room alone only with the light from his flashlight and his gun now just out of reach. The film closes by showing Jigsaw sitting in Matthews' van, as if he were dead but still smiling in triumph.
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