Crowley turns to Dean for help to locate the First Blade, the only weapon that can kill Abaddon. However, they soon discover that the trail leads to Cain... the Father of Murder and the most powerful demon of all time. Meanwhile, Sam asks Castiel for help when they need to extract the remaining grace from Sam's body to track Gadreel.

After the massacre at the ranch, Dean, Sam, and Castiel double their efforts to find a cure for the Mark of Cain but there is nothing in the lore that can help them. Desperate, Castiel comes up with an idea that Sam deems the "single worst idea I've ever heard." Meanwhile, Rowena continues to plot against Crowley, and Castiel tries to mend his relationship with Claire who is plotting revenge against Dean for killing her friend.

Despite Dean's directive to forget about looking for a cure for the Mark of Cain, Sam continues to do research. Dean suspects Sam is hiding something but decides to focus on a new murder case where they run into Cole. The three team up and learn a Khan worm is infecting men and turning them into murderers. Unfortunately, the worm makes its way into Cole.

Sam and Dean investigate a case where people are suffering violent deaths after hearing a mysterious song.

Hoping to find a weapon powerful enough to defeat Amara, Dean convinces “Castiel,” who is still Lucifer, to send him back in time to 1944 to the fated submarine mission that sunk the Hand of God. Meanwhile, continuing his charade with Sam while they wait for Dean’s return, Lucifer plans his next move.

Sam and Dean face their biggest challenge yet. Rowena makes her move.

When hunters gather together to celebrate the life and tragic death of one of their own, Sam, Dean, and Mary must take action when a demon starts picking off hunters one by one.

Sam enlists Rowena’s help to track down an old world, powerful family of witches after Dean gets hit by a spell that is rapidly erasing his memory.

When multiple patients of grief counselor Mia Vallens turn up dead, Dean, Sam and Jack investigate the mystery surrounding the murders and, each inadvertently, are forced to deal with unresolved grief of their own.