1

Spoiler Alert...

(For a 7 month old game.)

In the sense that the minimum required runs to beat Mum's heart is 2:

  1. Beat Mum - unlocks womb.
  2. Beat Mum's heart.

The following hand waving occurs:

  • You get the required deal with the angel/devil every time.
  • You win every run.
2

The absolute minimum run involves the following:

  • Defeat Mom - Unlocks womb
  • In a single run:
    1. Defeat Mom's Heart and get an angel room or devil room (Requires luck). Take the trapdoor/beam of light to Sheol/Cathedral.
    2. With a teleportation item, teleport to the I AM ERROR room (Requires extraordinary luck or a lot of teleporting) and take the trapdoor/beam of light to the Dark Room/Chest.
    3. Defeat The Lamb/Blue Baby - Unlocks the Mega Satan door
  • In the final run
    1. Find 2 angel rooms and, in each, bomb the angel statue and defeat the angel. This gets you Key Piece 1 and Key Piece 2, which combine to form the key.
    2. Do the same thing as in the previous run. When you reach the Dark Room/Chest, the Mega Satan door will be there, and the Key will unlock it.

The minimum run that requires as little luck as possible is:

  • Defeat Mom - unlocks Womb
  • Defeat Mom's Heart 10 times - Unlocks permanent entrances to Sheol and the Cathedral.
  • Defeat Satan 5 times - Unlocks the Negative
  • In a single run
    1. Find 2 angel rooms, as above.
    2. Beat Mom and get the Negative.
    3. Beat It Lives and go down.
    4. Beat Satan and touch the chest.
  • You'd need a third run in the first method. The Satan door doesn't appear until you've beaten The Lamb or ??? – Studoku Jun 6 '15 at 18:51
  • OK, I've fixed that – murgatroid99 Jun 6 '15 at 20:09

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