As Isaac is blindfolded, Isaac cannot use tears, and must rely entirely on Distant Admiration, Forever Alone, and bombs to deal damage.
Because Isaac starts with 3 Fly items, he will also begin the challenge as Beelzebub. This allows Isaac to amass a large number of friendly flies on the Basement floors.
The orbiting attack flies can be quite powerful, especially Distant Admiration when used properly. This will require optimization of Isaac's movement to maneuver into position to deal damage, as the flies are constantly moving, and avoid damage simultaneously.
Duct Tape can fix the position of the flies around Isaac, somewhat alleviating this.
Enemies that explode on death should only be targeted with Forever Alone, as destroying them with Distant Admiration will result in Isaac getting caught in their explosions.
Shops can carry BFFS! and Hive Mind, the former of which affects the damage of the orbiting attack flies and the latter of which affects the damage of the blue flies spawned from Beelzebub as well as the size of the orbiting attack flies.
Broken Watch and Stop Watch are good items to buy since they slow enemies down, although caution should be exercised with Broken Watch.
Obtaining Gnawed Leaf makes the challenge trivial as Isaac's orbiting flies still deal damage while Isaac is invulnerable. Obtaining it is highly unlikely, since there are no Treasure Rooms present.
It is not advised to reshuffle Isaac's items. As this will not remove Isaac's Blindfolded status, it is possible to reroll items in such a way that Isaac's orbitals are rerolled into useless items, thus making the run impossible to complete.
Black Powder is now effective on all enemies and bosses, making it a reliable source of damage without the precision required to deal damage using Isaac's orbiting flies, provided there is room to draw closed shapes.
Incubus acts as a replacement for Isaac's tears, thus indirectly removing Isaac's Blindfolded status.
Revelation can charge and fire regardless of the Blindfolded status, providing Isaac with an easy way to deal damage.
Pause can be used to great effect as it can permanently stop the movement of all enemies in every other room. Pairing this with items that help with recharging activated items, mainly 9 Volt, can guarantee victory.
It is heavily advised not to use Sacrificial Altar, as it removes both of Isaac's damaging orbital familiars. If no alternative source of damage has been obtained by then, or rewarded by Sacrificial Altar itself, the run will be rendered impossible.