该剧根据同名吸血鬼小说改编，故事讲述一架与地面失去通讯联络且没有任何生命迹象的波音777客机降落在肯尼迪国际机场，美国疾控中心生化威胁调查专家Ephraim Goodweather医生奉命赶到现场进行调查。他发现机上所有乘客都死了，但机上还有一种奇怪的新生物。不久后，他与纳粹大屠杀幸存者、退休教授A...braham Setrakian组建了一个应对此次危机的特别行动组。一群吸血鬼正快速将地球转变成他们的「进食场」，这个特别行动组成了人类最后的希望。该剧描述的吸血鬼与我们熟知的吸血鬼有很大的不同：他们是一种寄生生物！他们寄生在宿主身上，用尖刺来吸取血液，然后向宿主体内注入大量的幼虫。幼虫会释放出可怕的病毒，通过操纵宿主的基因让宿主的外貌发生巨大改变，从而诞生更多受到「主人」控制的「吸血鬼」。
在季终集里，Eph和Fet为实施最后的攻击行动而进行侦察，Setrakian向他们保证「这次行动一定能杀死吸血鬼主人」。Gus与一股奇怪的新势力结盟，这股势力的出现可能导致这场战斗向不可预知的方向发展。
Dutch计划将Eph关于吸血鬼瘟疫的警告以广播的形式公诸于众，但要实施这个计划需要冒很大的风险。与此同时，Eichhorst对当铺发动了攻击，Dutch和Eph等人面临新的威胁。一个独特的访客出现在Palmer面前。Gus为即将到来的战斗做最后的准备，但是他很快发现另一个神秘要素卷入其中。
Setrakian带领Eph，Fet和Nora追踪「吸血鬼主人」的巢穴。Zack和Mariela被迫留在当铺中，Zack为了救Mariela甘愿冒生命危险。
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