While in Rome visiting his sister Hayley, Jack tries to muster up the courage to kiss Dina, an American war correspondent and Hayley’s roommate, before returning to London. However, they are interrupted by Greg, Jack’s dorm roommate from university, who offers Jack a ride to the airport. After Jack and Dina awkwardly say their goodbyes, a frustrated Jack leaves with Greg.
Three years later, Jack is at Hayley’s wedding. Bryan, an aspiring actor and the “maid of honour”, is more concerned about impressing Italian film director Vitelli than assisting the bride. Amanda, Jack’s “nightmare of an ex-girlfriend”, has come to the wedding with her boyfriend Chaz, with whom she has clear commitment issues. Other guests include clingy Rebecca and socially inept Sidney.
Since their parents are dead, Hayley has asked Jack to walk her down the aisle. Just as they are about to, Hayley informs Jack that Dina has come to the wedding and is newly single. After the ceremony, Jack and Dina meet for the first time in three years. The two admit that they used to ask Hayley about one another.
Marc, Hayley’s former school classmate, arrives uninvited while high on cocaine, confessing his love for Hayley. She demands that Marc leave, before her husband Roberto shows up and invites Marc to stay for the celebrations. Hayley asks Jack to drug Marc with her sleeping drops and he reluctantly agrees. Shortly after Jack places the drops into Marc’s empty champagne glass, a group of children playfully rearrange the seating order. The narrator comments on the many variations eight people can sit at a table.
Following the rearrangement, the drugged glass ends up with Bryan, who quickly drinks it all. Jack arrives at the table and switches glasses, unaware that Bryan had already ingested the drops. While Jack and Dina reconnect, Marc blackmails Hayley by threatening to tell Roberto they had sex three weeks earlier. Hayley once again asks Jack to handle him, so Jack and Sidney lock Marc in a cupboard. A sedated Bryan mumbles through his maid-of-honour speech, before destroying the cake.
After a guest releases Marc from the cupboard, he grabs the microphone and exposes his affair with Hayley in front of all the guests. Upset, Roberto walks out on Hayley, but when she tries to stop him, he accidentally falls over a balcony. The scene freezes as the narrator reminds the audience of how the wedding can be affected by endless seating arrangements. In fast-forward, the film depicts a number of alternate scenarios where different guests are drugged each time, all ending in mayhem.
In the last scenario, Jack is finally sat beside Dina, though he is the one that ends up drugged. Unable to regurgitate the sedative, Jack asks Bryan to put his fingers down his throat. Dina walks in on the two, much to Jack’s embarrassment. They try to move past it back at the table, but as Dina tearfully opens up about her mother’s death, Jack struggles to stay awake, upsetting her.
Things soon being to look up for Jack and the other guests. Rebecca confesses that she likes Bryan for himself, not who he pretends to be, and the two hook up. Bryan gives a successful speech that impresses Vitelli. Following a conversation with Jack, Marc decides against exposing the affair. Instead, he wishes Hayley and Roberto the best and leaves. Amanda and Chaz realise they are not right for each other and part amicably. Sidney hits it off with an equally awkward woman, thanks to Jack’s advice.
As Dina is leaving the wedding due to a work emergency, Jack attempts to connect with her for the last time. She says that although the feelings were mutual, they missed their moment and leaves. After finally landing an opportunity with Vitelli, Bryan inspires Jack to take chances when they come. He takes off and chases after Dina, catching her at the end of the street. Just as he is about to kiss her, they are nearly interrupted by a man passing by who claims to know Dina. Jack tells him to go away and they finally kiss.
During the credits, other variations and mishaps are shown.