Although the show is based on the books of the same name, many of the characters are changed, though the main story lines are kept. Beginning in season one, ten characters received star billing, with one being written out and another being promoted.

Nina Dobrev portrays Elena Gilbert, the main protagonist, as well as Katherine Pierce, also known as Katerina Petrova, the main antagonist.Elena is quickly involved in a love triangle between two vampires, which serves as one of the main focal points of the show. Paul Wesley portrays Stefan Salvatore, one of the vampire brothers who is good-hearted and affectionate, the complete opposite of his older brother Damon Salvatore portrayed by Ian Somerhalder, the malevolent vampire brother who serves as the show's anti-hero.

Other cast members include Steven R. McQueen who portrays Jeremy Gilbert,Elena's younger brother, later revealed to be her biological cousin, with Sara Canning acting as Jeremy and Elena's aunt and legal guardian, Jenna Sommers. Katerina Graham portrays Bonnie Bennett, Elena's best friend and a witch. Candice Accola portrays Caroline Forbes, Elena's insecure friend and occasional rival, who becomes a vampire in the second season. Zach Roerig portrays Matt Donovan, Elena's childhood friend and ex-boyfriend, who later becomes romantically involved with Caroline. Michael Trevino portrays Tyler Lockwood, a werewolf, Jeremy's rival, Matt's best friend and son of the mayor of Mystic Falls; male members of his family have been shown to carry a lycanthropic trait. Kayla Ewell portrayed Vicki Donovan, Matt's troubled older sister and girlfriend of Tyler and then Jeremy. She was written out of the show in the seventh episode of the first season, after being turned into a vampire by Damon and killed by Stefan. Soon afterwards Matthew Davis joined the cast as Alaric Saltzman, a history teacher, vampire hunter, and love interest for Jenna.