Sam tries to move on without his brother and becomes hardened and more reckless in the way he hunts. Bobby and his psychic friend Pamela try to contact the other side to find out more about Dean's ultimate fate.
Castiel sends Dean back in time to 1973 where he encounters younger versions of his parents and for the first time meets his grandfather Samuel Campbell who holds a secret that sheds a light on the Winchester Family's connection to the hunter community.
A hunter named Travis points Sam and Dean towards a meat eating creature called a Rugaru. Complicating matters is the fact that Travis's target is a normal suburban dad in the earlier process of changing and he hasn't killed anyone yet.
Sam and Dean discover a Colorado small town's darkest secret as a wave of people fall prey to a "ghost sickness" that induces fear, paranoia, and ultimately a fatal heart attack. Sam and Bobby must figure out the cause and cure of the sickness when Dean himself falls prey to it.
Sam, Dean, and Ruby discover the existence of a female prophet named Anna Milton, who can hear the voices of angels and thus figures into the plans of a demon named Alastair who wants to use her as a tool against the angels.
Dean and Sam figure out why Castiel and his superior/handler, Uriel the Angel of Death, want Anna Milton dead when the three of them are forced to go on the run, not only from heavenly and vengeful angels, but from Alastair and his demon minions who also try to track down Sam, Dean, and Anna. With the assistance from the now-blind soothsayer, Pamela Barnes, they discover that 'Anna' is a fallen (former) angel and needs to seek her grace wings before the forces of both Heaven and Hell find them.
In an alternate reality mysteriously created as if Sam and Dean were never brothers and have never met, Sam and Dean work at a marketing office where they are forced to team up with one another when a series of mysterious suicides point to a ghost haunting the premises.
Sam and Dean are contacted by one Adam Milligan who claims to be John Winchester's son. The boys immediately suspect a demon trap and go to investigate. Adam turns out to legitimately be John's son and Dean is furious that John kept Adam's existence from them as well as sheltered Adam from the hunting life. Meanwhile other supernatural forces are at work, which lead to a tragic twist that neither Sam, Dean, or their new sibling could have guessed.
Castiel has been sent back to Heaven. His human host, Jimmy, tries to regain his life. But the demons won't leave him alone and now his family is at risk. Sam and Dean can help a little, but they're going to need a "miracle" to win.
Sam is becoming more and more inhuman. Dean and Bobby put him in the safe hold until he gets over his addictions. After Sam escapes with help, unknown to him, from Castiel, he finds Ruby and begins to feed once again. Dean begins to truly believe that the old Sam is gone for good.
When the last few of the 66 Seals are broken by Lilith's minions, Sam and Dean prepare for the big and probably futile fight in very different ways. Sam joins Ruby on a final attempt to kill Lilith before Lucifer rises, while Castiel and Zachariah tell Dean that it's time to play his part in stopping Lucifer.