Katie (Jenny McCarthy) tells Becca (Pamela Anderson) about a tape she saw which allegedly kills people seven days after watching it. Shortly afterwards, Becca finds Katie drowned, sitting in a chair.
In a farm outside Washington, D.C., Tom Logan (Charlie Sheen) is woken by a girl screaming. Tom goes outside to investigate and meets his brother George (Simon Rex). They discover a crop circle. When it's shown from above the circles make up an arrow with a sign pointing to the farm that reads "ATTACK HERE".
In Washington D.C., Cindy Campbell, an anchorwoman, goes to pick up her nephew Cody (Drew Mikuska) at school, who according to Cindy's friend and Cody's teacher Brenda Meeks (Regina Hall) has been having visions. George Logan arrives and invites Cindy and Brenda to a rap-off.
Cindy goes to Brenda's house that night and Brenda tells her that she watched the killer tape and needs protection. Tabitha the ghost comes out of Brenda's TV, knocks Brenda over and strangles her. Cindy finds her body.
At Brenda's funeral, Cindy gets the killer tape which Brenda watched and takes it home with her. George and Mahalik arrive and are told that they are at a wake. They mistake this for the fact that Brenda is not dead, and try to revive her.
Meanwhile, Cindy watches the tape and gets a call from Tabitha who tells her she will die in seven days. She calls George, CJ and Mahalik, and they rush to her apartment. CJ comments his Aunt Shaneequa is an oracle and she could help Cindy. She goes to see her and leaves George to look after Cody. Aunt Shaneequa (Queen Latifah) and her husband Orpheus (Eddie Griffin) agree to help and Cindy gives them a copy of the killer tape. After watching a segment of it Aunt Shaneequa discovers a backmasked picture of a lighthouse and she tells Cindy to find it.When Cindy returns home, Cody has just watched the tape.
At work, Cindy looks through various pictures of lighthouses and finds the one in the tape, but she leaves the tape behind and her boss grabs it. Cindy arrives at the lighthouse where she meets The Architect (George Carlin) who tells her the real story of Tabitha and how the killer tape got out in the world, The Architect had rented Pootie Tang but accidentally returned the killer tape in Pootie Tang's box. He also says that Tabitha was their evil daughter and that his wife drowned her in the family's farm well while he thought a time-out would have worked. Meanwhile in the White House, President Baxter Harris (Leslie Nielsen) and his main agent, Agent Johnson (Ja Rule) beging worrying about the Alien Invasion warnings that Cindy Campbell had given in the news show and after destroying a Mother Teresa award ceremony believing that a lot of people there were Aliens in disguise, Johnson and President Harris go to look for Cindy in the Logan Farm.
Upon arriving home again, Cindy discovers that her news show has broadcasted the killer in the airwaves for hours and now several people are in danger, she thinks things out and decidees to go to the Logan Farm where she knows the aliens will land. In the Logan Farm, Tom has everybody in the house go into the basement for refuge while he, George and Mahalik go outside to fight off the aliens. Suddenly, two aliens sneak up behind Mahalik, Tom and George when Secret Serviceman Jones and President Baxter Harris arrive and accidentally run them over. Baxter tells them he came looking for Cindy since he claims that she may hold the key in defeating the aliens. Baxter then notices the UFOs mistaking them as the Air Force in those "new round planes." Just as the UFOs get closer, CJ arrives with an army of rappers and among them are Master P, RZA, Raekwon, Method Man, Redman, Macy Gray and U-God. However, they have an argument and shoot each other dead.
After that, the aliens strangle Tom, George, Mahalik, CJ, Baxter, and Secret Serviceman Jones, Mahalik breaks free and knocks the head off of one of the aliens claiming "without their heads, they're powerless". The aliens' leader (voiced by Tom Kenny who also voiced the other aliens present) talks and reveals they came to earth because they need to kill Tabitha since they watched the killer tape, believing it to be Pootie Tang. When Mahalik asks why they were choking them, the aliens explain that strangulation is how they say hello. When George asks how they say goodbye, an alien kicks him in the genitals. Showing more of their oddity, one of the aliens shows them that they pee through their pointer finger which disgusts Tom at the moment that one of the aliens put his pointer in his mouth. President Baxter Harris quotes that the humans and aliens aren't that different after all and he pees through his pointer finger.
In the basement, Cindy recognizes a shot from the killer tape and then makes a hole in the wood and she finds the well where Tabitha drowned; suddenly Tabitha appears behind her. George goes to look for Cindy and then finds Tabitha attacking her, after a short battle Tabitha pretends the curse is broken so she can attack them (Cindy: "So you won't be evil anymore?" Tabitha: "Nah, I'm just screwing with ya!") but as she prepares to attack, President Harris opens the door behind Tabitha and knocks her into the well. (President, not realizing what he just did: "I just wanted you to know, we're all counting on you".) George seals the well and the curse is over. George and Cindy get married with everybody, including the aliens and Aunt Shaneequa, in the ceremony. As George and Cindy drive away they accidentally leave Cody behind. When they back up the car they are about to hit Cody but stop just in time; however, a car coming from another direction hits Cody and throws him through the air as the movie ends and the credits roll.

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