The movie begins with the Dreamworks logo and the boy sitting on the moon. A classic UFO swoops in and 'abducts' the boy. The sky explodes to show a planet with rings of rock, similar to Saturn, and the camera continues to move to another bluish planet. After five seconds the planet explodes, then a meteor from the planet's rubble hurtles past the camera, and we can see it is glowing. It starts to fly through space and heads to the Milky Way galaxy until it reaches Earth.
The scene switches to a US base in Antarctica in charge of finding UFO's. Inside a man is playing with a ping-pong ball that he bounces at the camera. He then notices an object on the radar and tells his co-worker who gets up and doesn't believe him until he looks at a different monitor and begins to overreact and calls in an Unidentified Flying Object to the government. They then track it's area to crash as Modesto, California.
The scene shifts again to the camera going through a house and looking at pictures of a woman with a man, obviously a couple. A flash keeps coming across the camera as it moves. We then see a light turn on in a room and three women surprising the woman in the bed. They get her to turn on the television where a weatherman is on the screen talking about the weather, then says it's a "great day to marry Susan Murphy" and tells the TV he loves her. Susan, the woman who was sleeping, returns the love to the television.
The scene shifts to Susan getting ready for her wedding. Her mother tells her she looks beautiful, while her mother-in-law Mrs. Dietl says they'll be Mr. and Mrs. Weatherman. From there Susan walks out to a gazebo and is met there by her fiancée Derek. They talk and Susan finds out they won't be going to Paris, instead they'll be going to Fresno as Derek got a job. He walks back to the church, while Susan hears a rumble and looks up to see a meteor coming towards her. She tries to run but is hit by it. Her mother comes to look for her, then takes her inside and cleans her up after the meteor hit. When she walks down the aisle, Derek uncovers her veil and tells her she is actually glowing green. Susan then begins to grow, and worriedly keeps asking Derek to help her and the people inside to relax. When she bursts through the roof she then begins to get subdued by the unexpected arrival of the military. They eventually shoot her with a sedative while the military evacuates everyone.
The scene changes, we see Susan waking up with a flashing red light above her. She calls out with no response, and then is transported to a large room with a table and chair, and she breaks the chair accidentally and tosses it away. A large amount of what looks to possibly be oatmeal is unloaded onto the table, when she hears murmuring. Three doors open but no one appears to be there. She then turns when she hears scurrying and eventually sees a cockroach, which she tries to squish with her spoon. The cockroach however asks her to stop and he then walks back onto the table. Susan sees a large amount of blue goop and picks it up, it then talks to her and so she tosses it onto the table as well. Then a green reptilian creature appears to which she screams. The three monsters begin talking about Susan, when she turns to run and runs into a large furry insect. The scream she lets out scares the insect in which the reptile has to then calm the insect down. Susan calls out for help when a door opens and a man named General W. R. Monger appears and tells her she will stay in the building from now on. She finds out the monsters names as she talks with the General. The insect is named Insectisaurus, the cockroach is known as Dr. Cockroach PhD, the reptile is known as The Missing Link, while the blob is known as B.O.B. She is then taken to her "room", told her name is now "Ginormica" where she curls into a corner and tries to sleep, saddened by her imprisonment.
Once again the scene changes to inside a large ship hovering over the previously destroyed planet. The ship speaks happily to begin reanimation sequence. A squid-like alien appears and wonders why he has been reanimated, and is then told that quantonium (an immensely powerful element) has been found on Earth. The creature, Gallaxhar, sends a robot probe to Earth to search and retrieve the quantonium.
The scene shifts to two teenagers on a date in a field, with the boy unwilling to have sex with the girl. The girl tries to take the lead when the car begins to malfunction and the roof goes back. The boy then sees a light in the back and thinks it's the police when an immense object crashes in front of them. The two then race to see what it is, and scream when a large light appears in front of them. The screen flashes white we then see several helicopters and army officials and the President. They have created a large staircase to the robot and the President walks up and plays a high paced song (a spoof of Close Encounters of the Third Kind with tons of jazzy funk beats, etc), but the alien then extends what looks like a hand and as the President reaches to shake the hand, it instead smashes the platform. The President then runs down the stairs as they crumble, then tells the Commander to "do something violent", and his helicopter lifts off.
The scene changes to a military briefing room, with the President being briefed on what they could do. He goes and puts his hand on a red button but the other commanders and advisors scream not to as it would launch the country's nuclear weapons. He then goes to the button next to it for a coffee. When he's asking what to do, General Monger interrupts and then jumps to the main floor. He then begins to tell the President about the different monsters, when a girl with papers continuously screams each time a new monster is shown. Eventually they remove her, but when they show Susan/Ginormica this time the President lets out a blood-curdling scream. Even though his advisors say not to, the President authorizes the Monsters to go against the Aliens.
The scene once again changes to the monster prison, the camera shows Susan strapped into a device that Dr. Cockroach has built in hopes of returning her to normal. It doesn't work, and then General Monger comes in to tell them that if they succeed they will be free. They are released outside of San Francisco where the alien robot is attacking. When Susan sees how big the robot is she hyperventilates and asks for a giant paper bag. Link and the Doctor tell her to hide in the city. The robot then begins to head towards the city and steps on B.O.B where he sticks to its foot. Susan is then slowly walking through the city when she hears a rumble and walks onto another street only to turn and see the robot. She begins to run until she decides to use cars as roller skates. Just outside the city Dr. Cockroach has constructed a fast moving rocket powered trolley car, which he picks up Link in. They try to plan to send Link into the machine to shut it down until Bob is flung into the trolley sending them to the back. It careens down and eventually runs off the dock, then comically drops into the water.
Outside the city, Susan is still running from the robot and eventually reaches the Golden Gate Bridge. As she roller skates through she accidentally causes a truck to flip over but as she tries to tell people to run, the robot returns on one side of the bridge and begins to pull it apart. B.O.B, Link and the Doctor appear but aren't able to help much, then Insectisaurus appears and shoots snot into the robot's eyes. Susan takes this time to tell B.O.B to eat the dividers so the cars can drive away. Link tries to attack the robot but is bounced back, and then Dr. Cockroach jumps onto the robot and gets inside the machine and tries to connect and disconnect wires. Susan gets grabbed by the robot's claw arm, but then is able to oddly open up the claw and push it back. She then takes hold of two of the bridge wires and ties up the robot eventually causing it to crash into the bridge and fall into the water. Susan then quickly grabs B.O.B, Link and Cockroach and races to another part of the bridge that isn't about to collapse. A piece falls and chops off the robot's head, deactivating it.
The scene changes to the alien ship where Gallaxhar is informed that the Quantonium was not taken. Gallaxhar orders the ship to head to Earth, where he will retrieve the Quantonium himself.
The scene once again changes to Modesto where the monsters are being dropped off. Susan returns to her home and introduces her new friends to her family. B.O.B believes that Susan's mother is Derek and hugs her causing her to be enveloped. He then spits her out when Susan tells him that her mother is not Derek, then apologizes to her mother saying B.O.B's a hugger. Susan asks where Derek is, finding out he's at the news station, then leaves to find him.
At the party B.O.B is flirting with a Jell-O, Dr. Cockroach continues to eat out of the garbage, while Link tries flirting with women and attempts to do a flip into the pool but instead crashes into the water on his side. Susan's family is frightened of the monsters, and when Link comes out crying from pain of chlorine, he scares the family off.
At the news station, Derek is doing his final good-bye to the station and viewers, and then asks the assistant if he did a good job. She screams and Derek looks to see a hand reaching in for him. Susan hugs and kisses Derek but then put him down finding out that she was crushing him. She talks to him but eventually realizes he was only interested in himself when he breaks up with her. She walks off clearly upset and tries to find her friends. She eventually arrives at a gas station and sits on the roof. Link, B.O.B and Dr. Cockroach join her and they talk about their night. Link, B.O.B and Dr. Cockroach help make her feel better talking to her and telling her what a great person she is. Insectisaurus roars approval as well. Then a beam comes down around her abducting her into a large spaceship. Insectisaurus shoots out snot to save her, but the ship shoots a large beam at him causing him to fall down, possibly dead.
Inside the ship, Susan asks Gallaxhar why he's here, and he replies that he needs the Quantonium to rebuild his planet on Earth. Angrily she tries to attack him, he runs and thinks he's safe until she breaks out of the cage and races after him breaking through doors to try and stop him. She is then caught in a glass cage, and as she tries to break out, she is drained of the Quantonium. When she is released, she then watches in horror as clones of Gallaxhar are made and armed.
Outside the ship inside a transport, Dr. Cockroach, B.O.B and Link are flying to save Susan. Monger tells them he'll be waiting outside for them, if he isn't he's either "dead or late".
The three then arrive in the ship and sneak around to try and find Susan. They see the clones being made and eventually see Susan being taken to the incinerator. B.O.B says that although he has no brain, he has an idea. We then see the three in line with the clones of Gallaxhar where they are then clothed in the same clothes of the clones. The scene then cuts to Susan, where B.O.B, Link and Dr. Cockroach walk up in the uniforms of clones and ask to take Susan. The clone thinks that Link is a malfunctioned clone and tells Cockroach and B.O.B to take Susan and Link to the incinerator. Cockroach asks for a gun, which the clone gives but Cockroach accidentally shoots him. The four then try to stop Gallaxhar and ask a clone where the main power core is. They then ask for another gun but accidentally shoot this clone alerting the others that the four are intruders. They race to the power core as the four fight the clones. Eventually entering the core, Dr. Cockroach steps onto a pad which is similar to Dance Dance Revolution. He begins to dance and eventually ends by saying his PhD is in dance, causing the self-destruct.
It then cuts to Monger and the transport waiting for the four. They are then attacked by the ship but are unable to avoid the blast. Eventually the ship crashes but General Monger holding his lieutenant lands on Insectisaurus' body, which is covered by a white thread-like covering, similar to a cocoon.
Back in the ship, Susan, Link, B.O.B and Dr. Cockroach are running trying to escape the ship. They see that the ship is falling apart, and they try to make it but are able to get Susan through the door, but wind up trapped on the other side. Susan tries to get through but without the Quantonium she is unable to. She then tries to find Monger and winds up in the robot bay.
In the cockpit, Gallaxhar finds out about the self-destruct and wonders why the ship can't still begin the invasion if there's six minutes to self-destruct. The ship then alerts him of Susan in the robot bay, so he activates the robots.
In the robot bay, the robots try to attack Susan who, while using hovering pads, is able to escape and inadvertently destroy the bay. She then uses the pads to head towards the cockpit, and while dodging the large blasts, she kicks a pad through the window and appears in the cockpit. She then fights against Gallaxhar and eventually, after poking him in the eyes, she shoots the ball above her that contains the Quantonium causing her to become Ginormica again.
In the main bay where the three monsters were trapped, they are now about to be crushed by machinery until Susan appears and gets rid of the machinery. She then picks up the three and dives off, and breaks through the bottom of the ship. Wondering where Monger is, Link reminds them that he said if he wasn't there, he was "dead", but the four then land on Insectisaurus who is now a butterfly, while Monger shouts "or late!". The seven fly off around the ship trying to escape.
It cuts to inside where Gallaxhar is in his escape pod attempting to escape. He is about to when the countdown reaches zero, but nothing happens. The ship wonders if it counted wrong when it explodes.
The five monsters, and two humans eventually land back in Modesto to the cheers of the people. They get off of Insectisaurus, where Susan hugs her parents, and her bridesmaids from the beginning of the movie scream. Link believes they are afraid once again, but instead the three leap into Link's arms causing him to fall over. Derek then appears asking for an interview with Susan. Instead Susan picks him up and flicks him into the air. She then has B.O.B go under where he's going to land and rescue him. He then spits him out and tells him it would never work and that he's found a Jell-O. The movie ends with the five 'monsters' being told that there is a giant snail about to attack Paris. Susan's glad she gets to visit Paris after all, despite it being to stop a snail.
There is something at the end where General Monger is inducted into the board of advisors we saw midway, but unfortunately I had walked out midway through it.
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