Sam and Dean Winchester are two brothers who, as children, lost their mother in a fire that had supernatural elements involved. The boys' father, now devoted to finding out the truth about what killed his wife, takes his sons on the road with him and teaches them to fight evil.

While Sam eventually left his life as a hunter to attend college, Dean remained with their father to help fight demons. When their father suddenly disappears, Dean seeks Sam's assistance to find him, and the brothers journey out together to investigate paranormal events and other unexplained phenomenon.