Warning: This page contains spoilers! Read at your own risk.
In the epilogue, the story of The Binding of Isaac at first appears to come to a close that parallels its Biblical source. It is in the same style as the intro and drawn by Isaac himself. Isaac's mother corners him and is about to sacrifice him, when the Bible falls off a shelf above her, hitting her and knocking her out. The narration references an angel intervening on God's behalf at the last moment, which is how Abraham's hand was stayed in the Biblical story as well.
The video then switches to a different perspective and style where Isaac has just put up his latest drawing on the wall. The door crashes open and his mother is in the doorway, brandishing her large kitchen knife, then the video fades to the credit sequence.
Upon defeating Mom, The Womb is unlocked, with the final boss being Mom's Heart/It Lives!. Each one shows Isaac unlocking a large Golden Chest, who promptly finds an Item, with the exception of the first, sixth and tenth endings.
Isaac finds Judas' Fez. This promptly unlocks the character.
Isaac finds a noose, and hangs himself with it. This unlocks the Transcendence item, which gives Isaac permanent flight.
Isaac finds a nail, and stabs himself with it. Afterwards, he turns into a demon and flies away from the screen. This unlocks The Nail item, which turns Isaac into a Demon upon activation, increases his damage, and gives him a Soul Heart.
Isaac picks up a Fetus in a jar, and turns to reveal himself wearing a top hat and a monocle, while a special sound effect plays. This unlocks the Dr. Fetus item, which allows Isaac to fire Bombs instead of tears.
Mom's voice calls out to Isaac from within the chest as he opens it. Her giant hand reaches out, grabs Isaac and pulls him inside. This permanently unlocks the "Everything's Terrible!" effect, which causes Champion Monsters and Bosses to appear more often, and makes Bosses drop less Hearts upon death.
Isaac finds a Wafer. This unlocks The Wafer item, which sets all types of damage to a half-heart.
Isaac finds a dead blue child in the chest. This unlocks the character ???.
Isaac opens a Golden Chest, like before, but rather than taking anything out of the chest, Isaac stands in front of it, flashing as all of the characters (Excluding ???) and a demonic version of him. Stepping into the chest, looking over his shoulder towards the closed door, Isaac closes the lid to hide from his mother.
Isaac is seen reading a Bible. He looks at the mirror to see a demonic reflection of himself. Accepting that he is corrupted with sin, Isaac closes the bible and gazes upon the Chest.
Defeating ??? will show the final ending, which shows various photos of Isaac and his family, including his dad. After the last photo is shown, the screen fades to black, giving a message saying "The End". For a short amount of time, there is also a faint message saying "Get in the box!", which is a reference to Time Fcuk, another game by Edmund McMillen.
- The sound effect that can be heard as Isaac flashes through his different incarnations in the Sheol ending is the same as the sound effect used in McMillen's game Time Fcuk when switching to a different layer.
- The fifth ending where Isaac finds Dr. Fetus is a reference to Super Meat Boy and the Dramatic Chipmunk meme.
- After Ending 10, the ending song changes to a haunted version of the "Jesus Loves Me" rhyme.
- The Bible will automatically kill Mom/Mom's Heart/It Lives! upon being used during the fight, which is probably a reference to Mom being knocked out instantly upon being hit in the head with a Bible in the Epilogue.
- Edmund McMillen has blogged about an article authored by a writer from the small indie game site, Twinfinite, saying that it is "By far the most mind blowingly accurate break down of the over-arching meaning behind the Binding Of Isaac's ending."