As a child, Growlie was James's only friend at his parents' estate. The two were inseparable, and Growlie often comforted James whenever he had problems, especially with his parents and arranged fiancée, Jessebelle. When the stresses of home became too much, James ran away, leaving Growlie behind at the mansion. Growlie lives in an extravagant doghouse, which was so large that Ash and his friends mistook it for being the family's actual mansion. Misty even commented, to her later embarrassment, that it was the largest mansion she had ever seen.
Years later, in Holy Matrimony!, James returned to his parents' home after hearing that they had died. However, this turned out to be a hoax, designed to trick James into marrying Jessebelle. After the deception was revealed, Jessebelle trapped James in the family's dungeon. Ash, his friends, Jessie, and Meowth released Growlie from his doghouse, allowing Growlie to burst into the dungeon and rescue its long-lost master. The two were thrilled to see each other, but their reunion was cut short by Jessebelle, who subsequently attacked with her Vileplume. After defeating the Vileplume and temporarily chasing Jessebelle off the estate, James once again left home, thereby giving up his inheritance and continuing to live with Jessie and Meowth. Before he left, he told Growlie to stay behind and watch after his parents, which greatly saddened the Puppy Pokémon.
In The Treasure Is All Mine!, Growlie inadvertently blew Team Rocket's cover. The trio had been infiltrating one of James's vacation homes; Growlie, elated to see its master once again, pounced on the group. Growlie proceeded to help James (once again) evade his ever-pursuing family. Though they rarely see each other any more, Growlie remains protective and devoted to its master.