Samantha Winchester is a college student bound for law school, determined to escape her family's past - unlike her older sister Deana. Ever since they were little, their father has been consumed with an obsession to find the evil forces that murdered his beloved wife and recruited his two young daughters to help him. They have grown up as hunters of the supernatural. Sam escaped this way of life after high school and now has a happy life with her boyfriend and a promising future career. Deana, however, stayed behind with her father to join him in his hunting.

After Deana arrives asking for Sam's help when their father goes missing, Sam must join her sister to find him. Her one-weekend trip to search for the missing John Winchester becomes an ongoing quest after a horrible tragedy ruins any thought of a happy life for Sam.

The two sisters, bound by tragedy and blood to their mission, travel across the country encountering terrifying and dangerous forces most believe to be nothing but superstition and folklore.