True Blood Season 1 - The main mystery of the first season concerns the murders of women connected to Sookie's brother, Jason (Ryan Kwanten). Maudette Pickens and Dawn Green are both strangled shortly after having been alone with Jason. Though Detective Bellefleur has little doubt that Jason is the killer, the town sheriff does not suspect him. Sookie's grandmother is murdered shortly afterward. At the end of the season it is revealed that Arlene Fowler's fiancé, Rene Lenier, is actually a man named Drew Marshall who has created a false identity, complete with Cajun accent. He has been killing women he considers "fang-bangers".

The True Blood Season 1 also focuses on Sookie's relationship with Bill and Sam's relationship with Sookie's friend Tara. Bill explains the rules of being a vampire to Sookie and, after killing a vampire to defend her, is forced to "turn" a young girl named Jessica into a vampire as punishment. In the last episode of the season, Jessica is left under Bill's care. After Maudette and Dawn's murders, Jason becomes addicted to vampire blood and has a short relationship with another addict, Amy Burley, which ends when she is murdered by Marshall. The season ends with the discovery of a body in Detective Andy Bellefleur's car in Merlotte's parking lot.