Seasons 1–5 Arc: Azazel killed Mary Winchester to feed baby Sam demon blood. Sam's demon-blood addiction is manipulated by the demon Ruby, leading Sam to kill Lilith—unknowingly breaking the final seal to release Lucifer from Hell. Sam and Dean learn they are the pre-destined vessels for Lucifer and Michael. In Swan Song, Sam regains control over his body and throws himself into Lucifer's Cage alongside Michael.
Seasons 6–10 Arc: Castiel absorbs souls from Purgatory, becomes corrupted by power, and briefly declares himself God before unleashing the ancient Leviathans. Dean takes the Mark of Cain to defeat Abaddon, dies, and transforms into Demon Dean. Upon removing the Mark, the brothers unleash Amara (The Darkness), God's sister.
Seasons 11–15 Arc: God (Chuck) returns, reconciles with Amara, and resurrects Mary Winchester. Lucifer fathers a Nephilim child named Jack. Chuck is revealed as the ultimate villain of the series—he has been manipulating Sam and Dean’s entire lives as his favorite written story. Jack absorbs Chuck's divine essence, stripping Chuck of His omnipotence and becoming the new, non-interfering God of the universe.
Series Finale ("Carry On"): Free of God’s protective narrative manipulation, Dean dies on a routine hunting call after being impaled on a rusty metal spike. He instructs Sam to live a full life. Sam marries, raises a son named Dean, dies peacefully of old age, and reunites with Dean in Heaven.