Upon entering the Boss Room, Satan will summon The Fallen to fight the player. He behaves exactly like the The Fallen anywhere else. However, a pair of Kamikaze Leeches also appear with him in the beginning of the fight.
This phase ends when the Fallen is killed, and will proceed to Satan's 1st form even if the leeches have not been destroyed.
An easy way to dodge his blood salvos is just standing behind the Satan Statue in the middle of the room, as The Fallen cannot fire through it. Otherwise, just follow the same tactics you would usually use for the Fallen.
When planting a Bomb about 3 seconds after entering the boss room where the Fallen appears (in front of the Satan statue), it should blow up the Kamikaze Leech, greatly damaging the Fallen and taking about a quarter of his health.
After defeating The Fallen, Satan comes out of the statue in the middle of the room and attacks the player. He has three attacks: firing two salvos of blood (first 5, then 4), firing a blood beam from his mouth (if his eyes are open before the attack), and firing a blood beam from each hand (if his eyes are closed before the attack). He only performs the latter two attacks if Isaac is standing directly in front of him.
One effective method of beating him is to stand on the very far left or very far right (occasionally switching if he gets too close) and dodging his projectiles while shooting at him. Focus more on dodging than where tears go (most will hit him). Note that while he is shooting his blood tears, he is incapable of firing his blood beams, so it's best to switch sides then.
Another tactic is simply to run in semi-circles around Satan, making sure not to stand still, while firing tears. This works best with a high Speed stat. Satan will continuously try to hit you (and ideally miss) with his blood bullets as you run around him.
After draining the HP of his first form, Satan will fly off screen. He attacks solely by stomping the ground in the same fashion as Mom. He will stomp continuously with two legs faster than Mom's foot. In addition, he respawns 2 Kamikaze Leeches. By dropping any extra bombs you have while he is stomping, you can do decent damage to him and possibly chain react with the Kamikaze Leeches.
In Hard Mode, the Eternal Satan fight starts with Eternal Fallen. During his 1st phase, he acts same as his normal counterpart, but shoots faster. During his 2nd phase, the Kamikaze Leeches he summons have a chance to be their Eternal Variants. He also spawns some extra Eternal Fallens (but they are smaller and act the same as normal ones).
Using The Bible during the fight against Satan will result in Isaac's instant death, unless he has The Wafer.
To get an early hit on Satan's second form, place a bomb as he starts to laugh during the transition from phase one to phase two. Wait for the shadow to appear, then move away. The explosion should damage Satan.
Satan's appearance is strongly reminiscent of Baphomet; the fictive deity that the Knights Templar were accused of worshiping.
His pose as a statue form and from his V.S artwork is a nod to Baphomet's artwork as well.
In the artbook, Satan's appearance look drastically different, being less bulkier, possessing a smaller body, curly ram-like horns, and possessing leathery wings rather than feathered. His cross-shaped mark from his forehead is also missing.
Half of Satan's attacks from the artbook are never displayed in the games. These include raining Mom's Knives, Harbinger-styled charge attack, and summoning a pair of Null-like demons.
When he transforms into form 1, he says Mom's "ISAAC"-line reversed.
When he transforms into form 2, his reversed laughter is the same as Mom's when she hits Isaac with her arm.
Satan can be fought after beating Mom the first time, by using The Joker Tarot card in The Womb 2. The Devil room contains a trapdoor leading to Sheol, bypassing the usual final boss Mom's Heart. If you manage to beat Satan using this method, it'd count as you've beaten the game twice instead of once, and you will unlock two endings/items instead of only one. This also applies if you manage to get the devil room after beating Mom's Heart for the first time then proceed to defeat him, with the additional benefit of giving you three endings instead of two.
In Satan's second form, if he is killed before he can stomp his feet two times, he will turn back into a statue, and it will be impossible to kill him.
This bug will not occur once Satan stomps his leg at least three times before being killed.
If Mom's Bra is used on Satan while his hoof is down, and he is then killed during the freeze effect, the Devil Statue will reappear and the player will be unable to do anything. Touching the Devil Statue will cause 1 heart of damage to Isaac. The same bug can also occur when using Mom's Contacts or Mom's Pad. Defeating the second phase of Satan with extremely high damage (one shotting the leg), will also cause this bug. Also, blood may continue to pour from the ceiling whenever the statue is touched. It is possible to overcome this bug and achieve a defeat of the boss by focusing a substantial amount of damage into the Statue which appears, eventually the encounter should end as normal.
If Isaac runs into the wall behind Satan's statue when he transforms into his 1st form, he will enter an invisible door into the Devil Room/Angel Room.
Satan transforming from his statue form.
Satan coughing up blood.
Satan vomiting up brimstone.
Satan shooting brimstone from his hands.
Satan dying and rising back up to his second form.
Satan's foot stomping down from above in his final form.