This is for beating the true final boss as Isaac. Reaching the boss isn't too hard, but the fight itself is the craziest gauntlet in the game.
First off you will need to have unlocked
Just play as normal up until the Depths/Necropolis 2. You'll see a door with a white square in the middle of it in the starting room. If you have an item that can let you teleport out of rooms, you can go fight Mom. But if not, there will always be a special skull somewhere on the map with an X on it, and blowing it up with a bomb will give you The Fool card, which teleports you to the starting room of the floor.
After beating Mom, grab either the Polaroid or Negative, then teleport out of the room. This is why you need a teleport item, as there's no exit from the boss room otherwise. Back in the starting room, walk into the strange door. The Polaroid/Negative will be removed from your inventory and slotted into the square on the door, and then it will open. Go inside and walk into the light.
You will begin the journey back upwards through every floor in reverse. You'll spawn in the boss room and have to find the "starting room" where a beam of light will take you up to the next floor. There will be no bosses, but enemies will still spawn as normal. Item rooms will not have any new pedestal items in them.
When you enter the light in Basement 1, you will be taken to an all new floor, Home. It's a small map with a preset layout and no enemies. You start in Isaac's bedroom, where you will find a chest you can open. Go down out of his room to the hallway. The room on the right will have a heart or two if you need it. At the bottom of the hall you'll head left into the living room, head more left to another hall. At the top of the hall will be Mom's room. There's a large chest below her bed, and if it's your first time opening it, it will contain
otherwise it will be a random item from the Mom item pool. Walk into her bed to go to sleep, and the map will transform in appearance. Head out of the room and back to the living room. When you walk in front of the tv, the final boss gauntlet will begin with Dogma.
In phase one, the tv is moved to the middle of the room, and Dogma is tethered to it. Shooting Dogma itself does nothing since it has a shield, all damage must be done to the tv. Dogma's attacks include:
Waves of Godhead style tears, the tears hurt you as normal, and if you stand in the light around them too long a beam of light will come down and hurt you
Bursts of tears around the room that sometimes will stop in place and linger for a while
A semi-homing Brimstone attack that curves towards you, and he can turn to face you if you move around him
A bunch of faded beams of light that aim straight at you, locking in place, then turning solid to deal damage after a second
After destroying the tv, phase two begins, and Dogma will take the form of an orb surrounded by feathers. It will fly all over the room and can be attacked as normal. Attacks now are:
Charging up for a moment and then shooting a wide spray of feathers at you
Holding an orb over its head that shoots the same faded lasers as phase one, but in random directions
Turning into a ring shape and dashing straight at you and off screen, scattering feathers all around it
After defeating it, another cutscene will play, and you will get the Dogma item, which gives you flight, a small speed and damage upgrade, and a one-time Holy Mantle shield. The rest of the battles take place in a horizontal shoot-em-up style. The bottom of the screen is lava and will damage you if you fly down into it. It's just like the crawlspaces, where "gravity" exists pulling things downward. This won't affect you since you can fly, but any minions that can't fly will be stuck down in the lava, and any sort of item drops that happen will drop the item down there too so you have to be quick to catch them. Now you will have to fight giant versions of the 4 Harbingers, with movesets similar to their normal forms, but super sized. Bosses will not have health bars showing anymore.
First is Ultra Famine. For his attacks, he will charge towards you and off screen, then reappear on opposite sides of the screen repeatedly, shooting bursts of tears. When he comes back to hang out on screen, he will slowly move towards you while bobbing up and down and spawning flies that will charge at you if you get too close to them. This will repeat until phase 2, where his body explodes and he will be left as a floating head. At this point his only attack is burst of tears in in six directions around him plus a couple straight at you.
When he goes down, Ultra Pestilence will appear next with a large swarm of flies near him. His first attack is a large green shot that shoots high in an arc and lands in the lava below. When it lands it splashes a bunch of green tears straight up, and some lava in a small wave, and will leave a pillar of poison that lingers for a while. If you stay in the poison cloud too long you take damage. He'll shoot this multiple times. His other attack is to fire a giant maggot out of his eye that shoots straight across the screen and loops back to fire out of the opposite side of the screen three times, then it will reverse and do the same until it's back in his eye. Repeat until phase 2, where his head will explode. Now he'll fire showers of green tears in a high arc like rain. He'll also occasionally shoot a giant ball of flies that will slowly follow you and spawn more flies as you shoot it. If you don't have good enough damage to get rid of it fast, just focus on the boss. When he dies, all flies die with him.
Next is Ultra War. He'll lob giant bombs at you that hurt on contact. They'll stop in mid-air and explode in a plus pattern across the entire screen vertically and horizontally, and burst out lines of tears in 12 directions like the hours on a clock. His other attack he will charge at you off screen, then charge across the bottom of the screen through the lava multiple times. Light beams will shine up from the lava to show where large lava balls will shoot upwards and then fall back down. Repeat until phase 2, where he loses his horse, gets angry and starts on fire. His first attack is to chase you down and do a lunging attack at your position, then immediately shoot flames across the screen in a plus pattern like the bombs, and also some scattered flames diagonally. His second attack he will hug a bomb and dash diagonally downward. When the bomb explodes it will again be the plus pattern, and he will also start bouncing off the sides of the screen and upwards, then drop into the lava. When he pops back out it will be the same giant lava balls popping out with him.
Finally after he dies, Ultra Death will appear. He only has one phase where he loops through his attacks. First he summons a bunch of scythes around him, they will all move directly towards him, then continue in the same direction until they fly off screen. Next, he will fly off screen, the come back moving very slowly while summoning a horde of giant invincible skulls that fly in the same direction in a wavy pattern. After a while, the skulls will all stop in place, and he will destroy them all and make the room very dark. 4 times in a row, he will move really close to you, then do a short swipe forward. Move up or down to dodge.
When he dies it's on to the FINAL final boss, The Beast. It's super huge taking up almost half the screen. First it will "chase" you through a bunch of stalagmite and stalactites, which will damage you on contact. I put chase in quotes because it gives the illusion of movement, but if you stop pressing any directions, the Beast doesn't actually get closer to you, it's just the other things that are moving towards you, sliding across the screen. When it stops moving, it will start inhaling, and big rings of fire will close in towards it, with a small gap in each for you to fit through. The moment the rings stop moving, get to the top of the screen, as it will fire a MASSIVE laser across the bottom 2/3rds of the screen. In phase 2, during the chase, sometimes stalactites will come loose and fall on you, giving you more stuff to watch out for. The ones that will fall will have a large crack in them so keep an eye out. Now when it stops chasing instead of the rings and laser, it will either shoot waves of fire and tears, or souls that will charge at you. When you reach phase 3, it will dive into the lava and pop back up. From here, it will chase you forever, and no more falling stalactites will appear. Just fire away and keep dodging spikes as the Beast starts falling apart and eventually dies.
An now take a breather, it's finally over.