Guide:Skeletron Prime strategies

Skeletron Prime is an absurdly difficult boss with high damage, HP, and defense values. It is best to prepare thoroughly ahead of time.

Equipment
If possible, a Megashark with Crystal Bullets make this a much easier fight (along with a ranged-type armor set). You need to kill The Destroyer first to get the Megashark. If attempting to fight Skeletron Prime alone, it is recommended you stick to ranged weaponry to better avoid Skeletron Prime's attacks. Rocket Boots, Spectre Boots, Angel Wings and/or Demon Wings are recommended for increased mobility. If no Angel/Demon Wings are available, be sure to equip a Lucky Horseshoe or an Obsidian Horseshoe to negate fall damage from the heights you can reach. You can also use a Featherfall Potion, or Gravitation Potion to compensate. It is also recommended that you have at least mythril armor before attempting the fight.

To put the boss's health in perspective - using the Megashark and Crystal Bullets, it takes 1500 shots to destroy the head. 261 shots will destroy the laser arm, 350 will destroy the cannon arms, 667 will destroy the vice, and 770 will destroy the saw. It's generally only worth it to destroy the laser and cannon arms.

An optimal build for fighting Skeletron Prime should be full Adamantine armor, preferably with the melee helm for the greater defense and movement speed. Accessories are left to preference, but should include some damage and speed boosts, and possibly defense.

PLight's Method
Both of the flying hardmode bosses are likely best solo'd by air while running primarily in one direction. As such, a two or three level skybridge made of wooden platforms running a significant length of the map would give the player a distinct advantage. While gravitation potions would effectively allow you to combat the bosses by air, it can be difficult to work out the leading with ranged weapons while flipping gravity, and Prime's motions are somewhat more predictable if running on a mostly level surface instead of flying all around. This is important - even if ammunition is not a limiting factor, time certainly will be. Once day breaks, his damage goes to over 9000 and his defense renders most of your attacks useless. Hermes Boots are required for the skybridge method - that or a handful of Anklet of the Winds and a Swiftness Potion or four. Any accessories you bring should be reforged to have greater combat power. A well-functioning build consists of full Adamantite armor (melee), a Hallowed Repeater + Cursed Arrows or Hellfire Arrows, a Megashark and/or Clockwork Assault Rifle + Crystal Bullets/Cursed Bullets/Meteor Shot (Crystals have splash damage, but less damage than cursed on average, and lack the Cursed Inferno debuff, while meteors can pierce multiple targets - which is useful for this boss as his orbiting limbs will often get in the way of your attacks), as well as an Adamantite Glaive/Excalibur if you feel like trying to melee. For potions, Ironskin Potions, Regeneration Potions, Thorns Potions, Swiftness Potions, and Gravitation Potions are all useful. Be sure to bring a stack of Greater Healing Potions as well. For accessories, I personally used Angel Wings, Spectre Boots, Obsidian Shield, Cloud in a Balloon, and Diving Gear, all of which had been reforged for defense or speed, and using this build I managed to get it down to 1300 health and kill the Prime Cannon and Prime Laser before sunrise, though I missed most of my shots. Using the outlined Skybridge method should make Prime easier to hit, however.