When a group of longtime girlfriends goes to Napa for the weekend to celebrate their friend’s 50th birthday, tensions from the past boil over.
Six old friends, Abby (Amy Poehler), Rebecca (Rachel Dratch), Catherine (Ana Gasteyer), Naomi (Maya Rudolph), Val (Paula Pell), and Jenny (Emily Spyvey) take a weekend vacation to Napa Valley to celebrate Rebecca’s fiftieth birthday, even though Rebecca keeps downplaying her birthday and insisting it’s just a vacation. Abby has recently lost her job but doesn’t tell anyone, Catherine is a successful TV chef who is constantly getting work calls and texts, and Naomi is a mom of four who keeps dodging calls from her doctor.
The ladies arrive to their rental home and meet the eccentric owner, Tammy (Tina Fey), who shows them around and warns them that they’re all going to devolve into wine-soaked fighting, which the girls dismiss. Abby is a little controlling and has a very tight itinerary, and so the women go to a dinner at a fancy local restaurant. Their waitress, Jade Maya Erskine), mentions that she’s recently broken up with her girlfriend, which piques Val’s interest. Before they leave the restaurant, the women spot Brené Brown and rush to ask her questions before politely getting asked to give her space.
After dinner, Catherine takes out some molly pills, but the girls are concerned about their various medications and decide not to do it and instead have more wine and dance. The next morning Abby is startled by Devon (Jason Schwartzmann), who Tammy neglected to tell the women “comes with the house” – he’s an in house chef and driver. Though everyone is very hung over, Abby has a tarot card reading scheduled on the itinerary. Lady Sunshine (Cherry Jones) arrives to do the reading. She tells Abby she’s adrift and panicking, Naomi gets the “death” card (meaning transformation… or death, Sunshine tells them), and Rebecca gets told she’s unmoving and done. She then reads the group, and tells them they need to shed the skins they’ve built up if they want to remain friends.
The women leave for their wine tastings, and Devon drives them to and from the vineyards. Catherine keeps taking work phone calls, Val worries about the text messages she sent to Jade, and Abby is concerned that Rebecca is not facing her fiftieth birthday. One of the vineyards has live music, and Naomi, wine drunk, commandeers the microphone and starts to sing “Eternal Flame”… and then falls off the piano.
Later on, Abby tries to wrangle the group for a drone photo, and gets very irritated when the women aren’t sticking to her itinerary. Rebecca goes to “offer her feedback” (her therapy term), and Abby begins picking at the other girls, which leads to some squabbling before tearfully confessing she lost her job. When the women leave, Abby throws the itinerary out the window. Val gets a text from Jade inviting her to her art show, so they head there. The entire art exhibit is a tribute to Fran Drescher and “The Nanny.” The wine ladies confront the young artists about the art being stupid while Catherine leaves to make another work call. Catherine runs into Tammy, who advises her that if her friends won’t let her talk about work they do not appreciate who she is. Meanwhile, Val thinks that she and Jade are having a moment, but Jade thinks Val is trying to buy a painting.
That night, Abby sleeps with Devon, and Rebecca throws her back out and is discovered by Naomi in the morning. She finally admits she’s scared of getting older and wants to make changes, and admits that she’s in a bad marriage and that her husband Brian sucks (which the other women have been saying the entire trip). Rebecca decides life is too short, and that they are going to do everything on the itinerary for her birthday, and the women wheel her out on a rolling chair. Catherine is missing, with the other women suspecting she abandoned them to do her new TV show. The women surprise Rebecca by recreating the pizza restaurant they all met working as waitresses at. They begin dancing when Catherine walks in furious about once again being left out, and Naomi gets extremely upset, saying Catherine makes herself left out when they all need her. Naomi admits that she got the BRCA gene test and is too scared to get her results, and storms out. When Abby tries to go after her, Rebecca asks her to admit that since she lost her job planning the birthday has given her the only sense of control she’s had, and that’s why she hasn’t listened to any of Rebecca’s wishes about the birthday, and that the weekend is really all about her. Abby storms out after Naomi, and all the women follow. As they argue, Naomi is bitten by a snake. With all the ladies unable to get signal, they all take turns rolling down the hill to get help – which fixes Rebecca’s back. Catherine decides to turn down the big TV offer she’s received because she wants to spend more time living in the present, but tells the others she loves working and that will always be a part of her – which they can’t hear from the bottom of the hill.
At the hospital, Naomi is told the snake that bit her was non-venomous. With the support of the other girls, Catherine calls back Naomi’s doctor, and they find out she does not have the BRCA gene. Val ignores a phone call from Jade, realizing she’s too cool for her. Tammy stops by with flowers and gives the women a ride back to the house. The women, including Tammy, who they invite to stay, finally just simply drink wine and relax and laugh together. Abby admits she slept with Devon – and so does Rebecca. They all celebrate Rebecca’s birthday, happy they came on the trip.