Misty grew up in the Cerulean Gym as the youngest of The Sensational Sisters, where she once strode into the mouth of a Gyarados as a baby and it closed before spitting her out, which caused her to become afraid of Gyarados. She was also left without dolls and having hand-me-down dolls. She eventually got tired of her sisters' personalities and left the Cerulean Gym at the age of 10 with her Goldeen, Staryu and Starmie to become at Water Pokémon Master.
In The Water Flowers of Cerulean City, Ash went to Cerulean City for his next Gym Battle, but Misty didn't want him to see that her sisters had turned the gym into an aquarium and were just giving out badges for free. However, Ash refused to listen to her and saw it. She then battled Ash as a temporary Gym Leader, but Team Rocket interrupted the battle and left it unfinished. However, Ash was given the Cascade Badge by Daisy because of their gratitude.
Misty originally just went with Ash so he could get a new bike for her. However, she forgot about the bike and used this as an excuse to travel with him and accomplish her own dream of becoming a Water Pokémon Master. She also seems to have a tendency to get friendships with younger characters such as Mikey, Sakura and Max, possibly due to her own condition with her sisters. She also captures a Horsea in Tentacool and Tentacruel after healing it from trying to stop a swarm of Tentacool and a Giant Tentacruel. She also accidently captures a Psyduck after escaping Hypnosis from the Pokémon Lover's Club's Hypno in Hypno's Naptime.
In Who Gets To Keep Togepi?, Misty wondered if the Pokémon Egg Ash found in Grampa Canyon would hatch into a Tentacruel or Lapras, when Team Rocket stole it. When the egg hatched, Misty swiped the egg from Ash and Brock right before it hatched, which caused Togepi to see Misty as its mother and refuse to go to anyone but her, despite the fact that Ash won the tournament fair and square. Pikachu agreed to help Misty look after it. She later leaves her Horsea and Starmie with her sisters later on. In the Indigo Plateau Conference, Misty temporarily became Ash's coach along with Brock.
She later coaches Ash again in the Silver Conference, but is later forced to use her old bike to return to the Cerulean Gym and take over after her sisters take a vacation. She leaves after beating the Invincible Pokémon Brothers and heads back to Cerulean City.
Upon arriving, Misty realizes that two Pokémon Inspection Agency agents were on their way and would shut down the Gym if there was no leader and rushed to the gym. To her horror, she saw that four boys on her sisters fan club had enraged one of the Magikarp raised at the gym and caused it to evolve into a Gyarados. She then attempts to conquer her fear of Gyarados after the accident in her childhood and teams up with Nurse Joy to return Gyarados to its Poké Ball. However, she is forced to trap Gyarados in a cage when the Invincible Pokémon Brothers show up and Kim challenges her to a battle to see who should be the Cerulean Gym Leader. However, Kai and Kail unleash theirTentacruel 3-on-1 against Misty's Corsola. She gains Gyarados' trust by protecting it from a Poison Sting attack and then takes over the Gym after Nurse Joy reveals herself to actually be Agent Joy from the PIA on inspection.
She later meets up with her old friend Sakura who wants a rematch for a badge, when she realizes her sisters ran out of Cascade Badges. She then gets a new set from Kinso after retrieving them from Pokémon gangsters and then has the first Gym Battle from Sakura and she wins with her Espeon. Misty then remains Gym Leader.
Prior to A Date With Delcatty, the sisters returned, but only Daisy remained. Misty showed Casey to a trainer called Georgio who wanted a date with her. After protecting his Delcatty from Butch and Cassidy, Misty returned to the gym with Togepi, leaving Casey to date Georgio. She then decided to meet Ash.
Misty comes over to Hoenn in The Princess and the Togepi and meets Ash, Brock, May and Max near the entrance to the Mirage Kingdom. Colonel Hansen then attempts to steal Misty's Togepi to take over the Mirage Kingdom and they learn that because Hansen is an impure-hearted human, his taking over of the Mirage Kingdom would destroy the Togepi Paradise in A Togepi Mirage!. The Togepi then come out from the Togepi Paradise and aid Misty's Togepi, using Metrenome to make Togepi evolve into Togetic. Misty then leaves Togetic with the Togepi in the Togepi Paradise before returning to Kanto.
In Luvdisc is a Mant Splendored Thing, she has another visit from Tracey and it is revealed they have two Luvdisc Pokémon, Caserin and Luverin. Luverin refused to date Caserin and left Luverin to be captured by Butch and Cassidy. They then rescue Luverin and Caserin from Team Rocket and they start a relationship that allows Daisy's next show to get on.
Horsea first appeared in IL019: Tentacool and Tentacruel, where it tried to warn Misty about the Tentacool, but they couldn't understand it. She captured and treated it, before a Giant Tentacruel attacked Porta Vista and Horsea tried to convince Tentacruel to stop, but failed. Horsea and Misty then teamed up to stop Tentacruel and Horsea remained on Misty's team.
Misty captures a big Seaking using her special lure, it nearly pulled her in so she sent out Poliwhirl it slaps Poliwhirl with its tail, nearly throwing it out of the boat, but Poliwhirl uses DoubleSlap and Misty captures it. It being 55kg and winning the battle means Misty wins the Seaking Catching Day, but under contest rules she releases it.
Misty befriended a Golduck on Kinnow Island and mistakes him for her Psyduck evolved. It obeys her, but then when Misty tries to put it back into his Poké Ball, but Psyduck pops out and Golduck runs off.
Misty borrowed Ash's Bulbasaur to participate in the Princess Pokémon Tournament. It was sent out after Pikachu got defeated by Lickitung's Lick. During the battle, Lickitung defeats Bulbasaur using the same techniques that it used on Pikachu.