Dean helliger sig familielivet med Lisa og Ben, men Sam dukker op igen og lokker Dean med tilbage på "jagtmarkerne". En rystende oplevelse tvinger Winchester-brødrene til at konfrontere den største trussel mod deres broderlige bånd, da de må kæmpe mod livsfarlige overnaturlige kræfter i denne fantastisk spændende sjette sæson med 22 afsnit på 6 discs.

Episoder:
01: Exile On Main St.
02: Two and a Half Men
03: The Third Man
04: Weekend at Bobby's
05: Live Free or Twihard
06: You Can't Handle the Truth
07: Family Matters
08: All Dogs Go to Heaven
09: Clap Your Hands If You Believe...
10: Caged Heat
11: Appointment in Samarra
12: Like a Virgin
13: Unforgiven
14: Mannequin 3: The Reckoning
15: The French Mistake
16: ...And Then There Were None
17: My Heart Will Go On
18: Frontierland
19: Mommy Dearest
20: The Man Who Would Be King
21: Let It Bleed
22: The Man Who Knew Too Much