Second War against the Darkness was a conflict fought between God and the Darkness and their respective allies. It started when the Darkness was released by Sam Winchester and Rowena through a spell, after the removal of the Mark of Cain.
God existed alongside his older sister, the Darkness. Despite his sister's disagreement, God created many worlds, in order to show her that there could exist other beings besides them, that could, in the end, turn out to be better than them. Refusing God's proposal each time, the Darkness destroyed all that he created.
Seeing her imprisonment as the only solution, God created four Archangels (Michael, Lucifer, Raphael, Gabriel) and barely succeeded in sealing her away by tricking her, the Mark of Cain serving as both lock and key.
Following the release of the Darkness, she automatically declared war to her brother and subsequently, to all of his creation. She started to torture and kill humans, in order to tempt God into revealing himself. Being unsuccessful, she captured God's favorite celestial, the fallen archangel Lucifer, and started torturing him. He was later rescued by the Winchesters. Dean acted as a distraction, while Sam rescued the heavily damaged Archangel. However, the Darkness realized something was wrong and almost killed Sam, Lucifer and Donatello, before God intervened and saved them.
After a failed attack on the Darkness, God is left mortally wounded and the universe dying with him. In a desperate attempt to balance the scales, Dean arms himself with a soul bomb to destroy the Darkness as well. However, Dean discovers that the Darkness has grown to regret her actions as despite everything, she still loves her brother. Rather than killing the Darkness, Dean convinces her to reconcile with God. The Darkness admits to God that he has created something beautiful and her attempts to destroy it were motivated by jealousy that she wasn't all there was to him anymore. God forgives the Darkness who heals the injuries she inflicted upon her brother. With peace established between the siblings, they depart the Earth together, but not before the Darkness resurrects Mary Winchester as a thank-you gift to Dean for reconciling them.