Sakata Gintoki is the lazy, sweet-loving, and deeply tragic protagonist of the Gintama anime and manga. A legendary war veteran known as the "White Demon," he now scrapes by running the Yorozuya business in an alien-occupied Edo. Despite his slacker exterior, he fiercely protects his loved ones. Recognizable by his signature naturally wavy, messy silver hair, half-lidded "dead-fish eyes," and wooden sword (bokuto) inscribed with "Lake Toya". Unlike typical protagonists who seek power and adventure, Gintoki is a man in his late twenties who is often broke, gambling, slacking off, and reading manga. Behind his cowardly, comedic antics lies an unbreakable samurai code. He will step up to fight any threat to protect his friends and the people of Kabukicho. He has an intense sweet tooth (which borders on diabetes), a massive obsession with Weekly Shōnen Jump magazines, and a crippling fear of ghosts.

Shinpachi Shimura is a core protagonist and the primary "straight man" (tsukkomi). He is a young samurai apprentice who works at the Yozoruya to learn the true way of the samurai. He is famous for his sarcastic retorts and his glasses, which are frequently treated as his entire identity. Because Gintoki and Kagura are so chaotic, Shinpachi acts as the moral and logical anchor of the group, delivering reality-checks and hilarious screams to ground the series' humor. He is highly dedicated to the sword, holding the legacy of his family's dojo. While often perceived as weaker than the main cast, he is surprisingly capable and steps up fiercely to protect his friends in serious arcs. Outside of his samurai duties, he is the fiercely devoted captain of the "Terakado Tsuu Imperial Guards," the fanclub for a popular pop idol.

Though she appears as a carefree, naive young girl, she is actually an alien belonging to the Yato Clan—the strongest, most bloodthirsty combat race in the universe. She works for the "Yorozuya" Odd Jobs shop alongside Gintoki and Shinpachi. She is loud, brash, brutally honest, and unladylike (often shown picking her nose or vomiting on screen). Despite this, she has a kind, fiercely loyal heart and a strong maternal instinct. Recognizable by her vermilion red hair tied in two buns, traditional Chinese cheongsam dress, and a purple parasol that she carries to protect herself from the sun. Endowed with superhuman strength, accelerated regeneration, and heightened reflexes. Because the Yato burn under the sun, she uses her parasol as a weapon. She has an insatiable appetite and a deep obsession with her favorite cheap snack, sukonbu (pickled seaweed strips).