With Sam inescapably trapped in Hell, Dean has no choice but to settle into a normal life with his girlfriend, Lisa Braeden. However, when supernatural occurrences begin in his neighborhood, Dean has no choice but to investigate... and discovers Sam is alive and well, and has brought family with him.
Sam investigates a case about missing babies whose parents are being murdered. At one of the crime scenes, he discovers a baby that was left behind and calls Dean for help. Reluctant to leave Lisa and Ben, Dean finally agrees to meet Sam and surprises his brother with how parental he has become. The brothers take the baby to Samuel, who decides to raise it as a hunter, which infuriates Dean. However, before they can decide the baby's future, a shape-shifter breaks in and attempts to kidnap the baby.
Sam and Dean call Castiel for help when they investigate a case about several dead police officers who seem to have been killed by the plagues of Egypt. Castiel confirms the staff of Moses was used to kill the cops and tells Sam and Dean that Heaven is in a state of chaos and God's weapons have been stolen. The three head off to find the thief and come face to face with an old enemy.
After Bobby discovers Crowley has no intentions of returning Bobby's soul, the hunter takes matters into his own hands. He calls on Sam and Dean for help after he unearths one of Crowley's deepest secrets. Meanwhile, Sam and Dean learn what Bobby does all day when they are not around.
While investigating a series of murders caused by vampires, one of them feeds Dean his blood. While Dean tries to fight off the compulsion to feed on humans, Samuel arrives with a cure... but it will require the blood of the vampire that converted him.
Sam and Dean investigate a series of suicides and discover the victims were being told brutal truths that drove them crazy. They find out someone is invoking the Goddess of Truth, Veritas, forcing people to be cruelly honest against their will and Dean is the next victim. Dean is forced to tell Sam the truth about how he feels about his return from Hell.
Dean becomes suspicious of Samuel's motives, but Sam isn't sold on the idea that their grandfather is doing anything wrong. The brothers go along on a hunt with Samuel and the other Campbells, but things go terribly awry.
Sam and Dean discover the Alpha skinwalker's plan: create sleeper cells of his kind and turn them loose upon humanity. To find and stop the Alpha, the brothers need the help of a skinwalker that has taken the form of a dog and befriended its human family.
While Sam and Dean are investigating a UFO sighting, Dean is abducted from a crop circle. However, when he awakens, he discovers he isn't dealing with aliens, but fairies! Unfortunately, only Dean can see the fairy that keeps attacking him which makes tracing and stopping them difficult.
Sam and Dean make a deal with Meg to find Crowley and force him to return Sam's soul, but the plan starts to fall apart when Castiel helps, and can't abide working with a demon.
Dean seeks out Death to help get Sam's soul back. Death tells Dean he will help Sam if Dean will agree to act as Death for 24 hours. Meanwhile, Sam decides he doesn't want his soul back and asks Balthazar for a protective spell to keep his soul out of his body.
Local virgins are being kidnapped by a dragon with massive wings, scales and a lair to keep its prey. It's up to the Winchester brothers to save the damsels-in-distress.
When Sam starts to have flashbacks from his year as a soulless hunter before he contacted Dean, the brothers receive a message leading them to a small town where Sam spent time working on a case with their grandfather, Samuel.
Ben calls Dean and tells him Lisa is in trouble. Dean leaves Sam to investigate a case alone and rushes home to rescue Lisa, however, he's not prepared for what meets him at the door. Meanwhile, Sam discovers the men that were murdered were all a part of a cruel practical joke played on a female co-worker who went missing.
Dean and Sam find themselves in an alternate reality where everyone believes they are two actors named Jensen Ackles and Jared Padalecki, who star in a TV show called Supernatural about two brothers who hunt monsters.
Sam. Dean, and Bobby set out in search of The Mother of All's latest monster. While investigating, they run into Samuel and Gwen, who are also hunting the creature. Samuel and Bobby get into a heated fight about how to handle the case.
The embodiment of Fate appears to eliminate individuals who survived because Balthazar has altered history and stopped the sinking of the Titanic. However, she soon sets her sights on Dean and Sam, who have avoided their fates once too often.
Dean discovers that Samuel Colt may have what they need to defeat Eve. Since Colt lived in the 19th century, the brothers ask Castiel to send them back in time to learn what they need.
Sam, Dean, Bobby and Castiel track Eve to a small town in Oregon. The guys discover the townspeople have been converted to demons, but surprisingly, they all appear to be dying. When they finally do meet Eve, she decides to torture the brothers by bringing back their mother, Mary Winchester, as a demon.
Castiel tells Sam, Dean, and Bobby about the war in Heaven and how he and Raphael became enemies. Bobby believes Castiel is hiding something, but Dean refuses to believe it.
A demon kidnaps Ben and Lisa to get to Dean. Sam and Dean are forced to join with an unlikely ally to free them.
The wall comes down in Sam's head and all hell breaks loose. Dean and Bobby are, for once, at a total loss on how to help him and are forced to stand by and do nothing while Sam breaks. The battle for Heaven comes to a head.