While Ash and his friends continue to make their way to the Violet Gym, they find themselves looking for a place to spend the night in a quiet area called Happy Town. Tired, hungry, and dirty, Ash knocks on the door of a locked Pokémon Center and, to his surprise, is greeted by a Blissey. After noticing Ash's hunger, Blissey tries to give Ash some sweets, but ends up spilling it on Ash. While washing it off, Blissey suggests that she wash his back, but ends up scratching him. While she tries to attend to the scratch, she puts too much alcohol on him, and in the end, he is in a full-body cast. Nurse Joy eventually wakes up and apologizes for Blissey's trouble.
Outside, James devises a plan to sneak into the Pokémon Center and steal some Pokémon and some food for the equally hungry Team Rocket. However, once they get inside, they find themselves in an empty kitchen with nothing to eat. Meowth finds a parsnip in the fridge, but refuses to share it and runs off. Jessie goes looking for him, but finds a Blissey in the hallway. The Blissey tackles Jessie in joy; Jessie initially thinks that she tackled her to stop her, but then notices that Blissey's egg necklace has only its upper half. Jessie pulls out the bottom half, connects the pieces, and then remembers Blissey.
Jessie explains to James and Meowth that, when she was young, she wanted to become a Pokémon Nurse, but she could not get into a regular nursing school. She noticed a flyer for the Pokémon Nurse School, which was intended only for Chansey, and decided to go there, despite being advised not to. Jessie was the only human in the class, the rest being Chansey. She was competent at nursing and helped out a Chansey who kept messing things up by showing her how to wrap bandages, among other things. The two quickly became friends. However, while Jessie was good at most nursing skills, she could not resist Chansey's Sing, and fell asleep when she was supposed to be singing sick and injured Pokémon to sleep herself. She eventually gave up on nursing and failed to graduate, but her friend Chansey did. On graduation day, each Chansey was given a nurse's hat and an egg-shaped pendant. As Jessie was leaving, she was approached by her friend, who first tried to give Jessie her hat; Jessie refused to take it, so she gave her half of her pendant so that they both had something to remember each other with.
Overjoyed to see her friend again, the evolved Blissey satisfies Team Rocket's hunger by giving all of the food from the Center storeroom, much to Jessie's reluctance. The next morning, Ash and his friends discover only a tiny amount of food left in the Center. Ash complains to Nurse Joy about the lack of food. She checks the storeroom, only to find it empty. Nurse Joy reviews the security tapes to see who took the food, which expose Blissey as the culprit. Nurse Joy asks Blissey to explain why she took the food, and says that it could end Blissey's career as a nurse.
Watching this through their binoculars, Team Rocket devises a plan to get Blissey out of trouble. They decide to go back and tell them they tricked Blissey into giving them food. They land their balloon in front of the Center and announce over a megaphone that they accidentally dropped all the food that they stole. Once they have everyone's attention, they demand that all of the Pokémon in the Center be handed over to them, or they won't return the food. While Ash and Nurse Joy argue with them, Blissey comes outside and runs over to Jessie. Jessie pleads that Blissey not reveal their friendship in an attempt to save Blissey's job. Blissey doesn't care and continues towards Jessie, who sends out Arbok and Lickitung to keep Blissey at a distance. Despite this, Blissey still wants to be with Jessie, so Jessie forces herself to order Arbok and Lickitung to attack Blissey. After they do so, Jessie yells at them for hurting her.
However, Blissey gets back on her feet and walks toward Jessie again, still unaware of why Jessie wants to keep her away. Jessie then orders her Pokémon to attack Blissey again, lightly this time. Even after that, Blissey limps toward Jessie, refusing to turn away. Then, Jessie shoots the ground with a rocket launcher, and threatens to hit her with the rocket if she comes any closer. James begins to insult Ash for letting a Blissey do all the fighting, while Meowth uses a pair of grabbers to steal Pikachu. Pikachu immediately uses Thunder Shock to release himself, zapping Team Rocket.
Nurse Joy then runs to Blissey and apologizes for doubting her. Blissey then looks to Jessie, who puts her finger over her mouth. Still hungry, Ash sends out Squirtle and Chikorita to retrieve the food. Pikachu uses Thunderbolt on Arbok; Chikorita uses Vine Whip on Lickitung; and Squirtle uses Water Gun at Jessie, James, and Meowth. The trio runs to the balloon right after the attack, but Chikorita uses a Razor Leaf to pop the balloon and cut the food from it, sending the food to the ground and sending Team Rocket blasting off into the ocean.
In the aftermath, Blissey serves a whole meal to Ash and his friends. Meanwhile, Team Rocket remains on their capsized balloon basket, pleased with themselves that they helped Blissey, but depressed that they didn't get any food.