NOTE: This spoiler was submitted by Jeremy

The film opens in the town of Taylorsville, where a young boy named Yoyo (Reyn Doi) is doing his newspaper route until he reaches a tree with a mechanical owl that scans him. He enters the tree, which takes him into a secret underground facility run by the mad scientist Sharon Gordon Fisherman (Kristen Wiig). Her top scientist (Patrick Bristow) has made genetically enhanced mosquitos that are meant to kill animals with rabies, but Sharon plans to use them against people. She orders the scientist to be taken away and thrown into a room with the mosquitos. Sharon declares that nobody can stop her.

In a small Nebraska town are best friends Barb (Annie Mumolo) and Star (also Kristen Wiig) at their workplace, Jennifer Convertibles. They are talking about their favorite things, such as their preferred pants (culottes), until a young couple asks if they can buy the couch that they are sitting on. The two make an excuse for them not to be able to take it since they consider it their own personal couch. The ladies’ boss (Ian Gomez) calls them in to announce that the store is shutting down, and they are losing their jobs. Dismayed, Barb and Star leave the store and run into an old friend, Mickey (Wendi McClendon-Covey). She tells them how she has felt more alive than she has recently after visiting the Floridian town of Vista Del Mar.

Barb and Star host a “talking club” with friends Debbie (Vanessa Bayer), Pinky (Fortune Feimster), Delores (Phyllis Smith), and Bev (Rose Abdoo). Debbie is snobby and shuts out one other member, Gail, for being late. They bring up the topic of their jobs, and she is rude to almost everyone who talks. When they get to Barb and Star, they lie about their jobs until they come clean and admit that they lost their jobs. Debbie makes the other women leave because Barb and Star broke their “no lying” rule. Feeling that they have hit a rut in their lives, the ladies decide they should take the trip to Vista Del Mar.

Sharon orders her henchman, Edgar (Jamie Dornan), to take a microchip with her that can be used to activate the signal to draw the mosquitos to Vista Del Mar where she will enact her revenge. Edgar is in love with her, but she just manipulates his feelings to keep him under her thumb.

The ladies hop on the next flight out and spend the whole flight talking about their favorite name, Trish, and imagine an entire story about a woman named Trish who became a water spirit. They arrive in Vista Del Mar and go to the very luxurious hotel, where they walk in on a musical number and the staff delivering goodies until the ladies realize that they are supposed to be staying at a MOTEL. They end up walking back and find the rooms aren’t nice and the pool is empty, so they can’t cool off from the heat. Barb and Star decide to sneak over to the hotel’s pool, where they are caught by the manager (Michael Hitchcock), but he tells them that there is now a vacancy since the family from that room “disappeared”.

Barb and Star admire their new room before deciding to head out and enjoy the place. After visiting some gift shops, they meet Edgar at the bar that night. They share a large drink bowl that where the “treasure” at the bottom is syrup and pills that cause them to start tripping out. The trio has a wild night that ends with them waking up the next morning to find that they had some kind of orgy.

When they wake up in the morning, Edgar reports back to Sharon and threatens to turn on her if she doesn’t show reciprocate his love. After he leaves Barb and Star, he realizes that the microchip he was carrying that would create a signal for the mosquitos is missing, which he lost during his night with Barb and Star. In his despair, Edgar runs to the beach and has his own musical number where he spills his heart out.

The ladies pretend not to remember Edgar when they both secretly pine for him. Barb pretends to take a bath and sneaks out the window to meet Edgar. Meanwhile, Edgar is called by Sharon’s backup henchman, Darlie Bunkle (Damon Wayans Jr), who gives more information about himself than he really should. He is there to offer assistance as discreetly as he can be (which is to say, not very). Barb shows up at Edgar’s door, and they spend the afternoon together, all while Darlie is taking surveillance pics of them. Before they can take things any further, Barb remembers that she left the water running to fool Star, so she returns to the room and finds Star asleep…except that was a dummy so that Star could now sneak over to Edgar’s room. They do the exact same things that he did with Barb (with pics being taken too), but Star succeeds in hooking up with Edgar again. She goes back to the room and finds that Barb figured out her trick, but they end up lying to each other about where they really ended up going.

Sharon explains her tragic backstory to Yoyo – she was born with a rare skin disease that made her allergic to the sun and gave her an extremely pale complexion, earning her ridicule from all her classmates. Her only friend was a girl named Maria who got eaten by an alligator on the way back to her house. Later on, Sharon was jokingly crowned Shrimp Queen at a festival in Vista Del Mar, in which she was shot out of a cannon and fell naked into the pool of a cruise ship. From that day forward, she vowed revenge against the town and everyone in it.

Star pretends to be sick so Barb can go out and enjoy herself while Star continues to hook up with Edgar. Barb enjoys time at the beach and with a local group of people before she is taken back to the resort by a man calling himself Tommy Bahama (Andy Garcia). Star finds herself conflicted with going behind Barb’s back, and after talking to a crab that sounds like Morgan Freeman (but isn’t really him), Star decides to be honest with Barb. However, Barb catches her and Edgar together first. When she goes to confront them, she overhears Edgar alone in his room talking to Sharon about the whole scheme to attack the town. She in turn tells Edgar that Barb and Star are spies, per Darlie’s pictures sent to her. Edgar catches Barb outside and thinks she really was spying on him and betraying him.

Edgar follows her back to their room and ties them up. They ask him why he’s planning to kill the town, and while he gives his own backstory, the ladies try to escape, but to no avail. After Edgar leaves the room, Barb and Star free themselves, but they are greeted at the door by Sharon, who punches both of their lights out.

The villain brings Barb and Star to the edge of a cliff, where they must choose between death by plunging off a cliff onto jagged rocks, or get eaten by alligators. After Sharon leaves, Barb and Star back up from the gators as they continue arguing. Seeing no other choice, they jump off the cliff, but thankfully, their culottes make good parachutes. They reconcile and head off to stop the evil plan.

After recovering the microchip, Sharon gets ready to get her revenge, but Edgar has a change of heart and tries to stop her. The signal is placed in the middle of the Seafood Festival taking place, but he can’t deactivate it. He runs into the middle of the festival where he reunites with Barb and Star, and he joins forces with them to stop the disaster. Edgar plans to take the signal far away into the ocean and take the antidote to protect him from the mosquitos but then finds that Sharon just gave him iced tea. Darlie comes to stop them, but Edgar fights him and has Barb and Star run off. They hop on jet skis and try taking it out into the ocean. Yoyo unleashes the mosquitos to head to the festival, but Sharon notices that nothing is happening. She knows what is going on and she launches herself with the cannon toward the ocean to get Barb and Star. They fight and Sharon gets the signal back, but Barb took the keys out of the jetski. The mosquitos head in their direction and the ladies dive underwater as the mosquitos swarm around Sharon. Barb and Star resign themselves to drowning together until they see a mysterious light shining toward them.

The people at the festival watched the scene unfold and think Barb and Star are dead, until they are saved and brought back to the shore by none other than a water spirit named Trish (Reba McEntire). Edgar and the others praise Barb and Star as heroes, and Edgar makes it official with Star. Sharon comes back, having taken the real antidote but is covered in bites. Although she is angry, she admits that she has never had a friend. The festivalgoers, along with Barb and Star, all vow to be her friend, and she has a change of heart. Barb and Star then spend the afternoon together riding a banana boat.

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Midwestern best friends Barb and Star are let go from their retail job when the company closes down. After a run-in with an old friend, the two decide to take a much-needed vacation to the beachside town of Vista Del Mar. Little do they know, a mad scientist named Sharon Gordon Fisherman is planning revenge on the town for ridiculing her as a child for her skin condition by unleashing a swarm of deadly mosquitos on them during a Seafood Festival.

Barb and Star meet Edgar, Sharon's henchman who is in love with her, but she only manipulates his feelings for her gain. Both ladies take to Edgar but he and Star truly fall for each other. Barb discovers Edgar's plan with Sharon, but the villain convinces Edgar that the two are spies, and that he can't trust them. Sharon finds Barb and Star, and takes them to a cliff to try and kill them, but they survive and head off to stop the plan.

Edgar has a change of heart and joins forces with Barb and Star. The ladies take the signal for the mosquitos into the ocean, but Sharon goes after them. Barb and Star trap Sharon on the jetski to get stung by mosquitos, and they are taken back to land by a mermaid (er, "water spirit") named Trish (which happens to be the ladies' favorite name). Star and Edgar become an official couple, and Sharon survives the mosquitos because of the antidote, but she has a change of heart when everyone says they will be her friend. Barb and Star then continue making the most of their vacation.