The two recurring actresses are Anna Faris and Regina Hall as Cindy Campbell and Brenda Meeks, respectively, appearing in all installments except the fifth film.

After a group of teenagers (consisting of Cindy Campbell (Anna Faris), Bobby Prinze (Jon Abrahams), Buffy Gilmore (Shannon Elizabeth), Greg Phillipe (Lochlyn Munro), Ray Wilkins (Shawn Wayans), and Brenda Meeks (Regina Hall) accidentally hit a man with their car, they decide to dump his body in a lake and never talk about it again.

This is the last installment to receive an R-rating and also marked the end of the Wayans siblings' involvement with the franchise, until the development of the sixth film.

Greg, Buffy, and Bobby are replaced by Buddy (Christopher Masterson), Theo (Kathleen Robertson), and Alex (Tori Spelling).

The film then merges into a parody of House on Haunted Hill (1999) with the story beginning when a perverted college professor, Professor Oldman (Tim Curry) and his wheel-chair bound assistant, Dwight (David Cross), plan to study ghosts inside a haunted mansion with the clueless teens as bait.

Cindy falls in love with a rapper named George (Simon Rex), a parody of Jimmy "B-Rabbit" Smith Jr. of 8 Mile (2002), when she hears that she is to die in seven days.

Meanwhile, George and his older brother Tom (Charlie Sheen)—the farmers who discovered the crop circles in their corn field—learn that extraterrestrials are coming to Earth to destroy the killer responsible for the deaths of those who have watched the tape.

There are video cameras to record the events, and Jody and Dan soon discover that a powerful creature known as "Mama" is haunting them, trying to claim their newly adopted children.

The rest of the film contains traces parodies of The Exorcist (1973), The Amityville Horror (1979), Poltergeist (1982), Titanic (1997), What Lies Beneath, Hollow Man, and Charlie's Angels (all three 2000).

Scary Movie 5's central areas of satire are the Paranormal Activity films (2007–2021), Black Swan (2010), Rise of the Planet of the Apes (2011), and Mama (2013).

Other notable parodies are those of the Madea films (2005–present), Inception (2010), Fifty Shades of Grey, The Cabin in the Woods (both 2011), Sinister (2012), and Evil Dead (2013).