In the opening scene, Harold Cooper (Kevin Kline) is bathing his two-year-old son when his wife, Sarah (Glenn Close), receives a phone call at their Richmond, Virgina home telling her that their friend, Alex Marshall (an uncredited Kevin Costner), has committed suicide by slashing his wrists in the bathtub of their vacation house in South Carolina, where he had been staying.
At the funeral, Harold and Sarah are reunited with college friends from their days at the University of Michigan. They include Sam Weber (Tom Berenger), a famous television actor now living in Los Angeles; Meg Jones (Mary Kay Place), an unhappy, chain-smoking former public defender who is now a real estate attorney living in Atlanta and wants a child; Michael Gold (Jeff Goldblum), a sex-obsessed 'People' magazine journalist living in New York City; Nick Carlton (William Hurt), a Vietnam War veteran and former radio host living in Chicago who suffers from impotence and who also struggles with a drug addiction (involving cocaine, quaaludes, and various painkiller pills) due to a war injury (implied to be in his groin which is the result of his impotence); Karen Bowens (JoBeth Williams), a housewife from suburban Detroit who's unhappy in her marriage to her advertising executive husband, Richard Bowens (Don Galloway), an outsider. Also present is Chloe (Meg Tilly), Alex's much-younger girlfriend at the time of his suicide.
After the burial, everyone goes from the cemetery to Harold and Sarah's vacation house, where they are invited to stay for the weekend. During the first night there, a bat flies into the attic while Meg and Nick are getting reacquainted. When Meg tries to seduce Nick, he responds: "Did I ever tell you what happened to me in Vietnam?" The men are forced to team up to try to remove or kill the bat.
Later that night, Sam finds Nick watching television alone in the living room and they briefly talk about Karen. The two then go into the kitchen for a midnight snack and find Richard, her husband, already making a sandwich for himself, and the three of them make small talk which turns into a discussion about responsibility and adulthood. At the end of the discussion, Richard states "Nobody said it was going to be fun. At least, nobody said it to me."
The next morning, Harold and Nick go jogging. Harold tells Nick that his business of running shoe company is about to be bought out by a large corporation, and that he's about to become rich. Harold confides with Nick that Sarah and Alex had an affair five years earlier. Nick comforts Harold by saying, "She didn't marry Alex."
Richard returns home to look after his kids, but Karen decides to stay in South Carolina for the entire weekend. Nick, Harold, Michael and Chloe go for a drive while Sam and Karen go food shopping. Back at the house, Meg reveals to Sarah that she wants to have a child, and that she is going to ask Sam to be the father, knowing now that Nick can't.
Out in the countryside, Harold listens to Michael's plans to buy a nightclub in New York.
Chloe takes Nick to the abandoned house that she and Alex were going to renovate. She tells him that he reminds her of Alex, to which Nick replies, "I ain't him."
During dinner, Sarah starts tearing up over Alex as the group talks about him. Harold puts "Ain't Too Proud to Beg" by The Temptations on the stereo and everyone dances while cleaning up the dishes. While the others sit around and get high from smoking pot, Meg asks Sam to father her baby, but he declines.
The next morning, Nick, Sam, and Harold go jogging, and the subject of Alex's suicide comes up again. Harold's surprise arrives: sneakers for everyone to wear during the upcoming Michigan football game. The group, minus Nick, watches the game on TV while Sarah tells Karen about her brief affair with Alex and how it affected their friendship negatively.
During the game, Michael offers to father Meg's child, alluding to the fact that they had sex many years ago during the 1963 March on Washington in their college years. At halftime, Chloe, Sam, Harold, and Michael go outside to play touch football. Nick returns, with a police car following him. The officer says that Nick ran a red light and was belligerent, but says that he will drop the charges if Sam would hop into Nick's Porsche as his TV character, J.T. Lancer, always does. Sam is unsuccessful and hurts himself, but the officer drops the charges anyway and apologizes to Harold.
Karen later tells Sam that she loves him, wants to leave Richard and live with Sam and her two sons. When they kiss, Sam pulls away and tells Karen not to leave Richard, as she will regret it in the long run. He confesses that it was "boredom" that caused his own marriage to fail, and he doesn't want her to make the same mistake. Karen feels misled and angrily storms into the house.
Harold is on the phone with his daughter, Molly, and lets Meg talk to her. Observing their interaction on the phone, Sarah decides to let Harold impregnate Meg, but does not tell him yet.
The group once again discusses Alex. Nick says, "Alex died for most of us a long time ago," but Sam disagrees and leaves. Karen follows him and the two have sex outside. Sarah tells Harold about Meg's situation while Chloe and Nick go to bed together, even though he warns her of his condition. Meg and Harold then have sex. Meg says "I feel like I got a great break on a used car." In the living room, Michael and Sarah joke around and interview each other with a video camera.
In the morning, while Karen is packing her clothes, she subtly tells Sam that she has decided to stay with Richard. At the breakfast table, Harold reveals that Nick and Chloe will be staying in the guest house for a while so they can renovate the old abandoned house for them to live in. Sam and Nick then make up from their argument the night before. Nick gives Michael an old copy of an article he wrote about Alex back in college. At the end of the movie, Michael states, tongue-in-cheek, "Sarah, Harold. We took a secret vote. We're not leaving. We're never leaving!" They all laugh and "Joy to the World" by Three Dog Night plays as the end credits roll.