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I found explosives - especially mini nukes - to be really useful when taking on highly populated areas like settlements and high-level enemies like deathclaws at a relatively low level. I also found melee/unarmed weapons to be useful because killing everything on sight can burn through tons of ammo.
A high Medicine skill can be useful for the increased effectiveness of stimpaks, especially on hardcore. Survival can also be a useful skill for increased food effectiveness. The perk Them's Good Eatin' can also be a solid option for healing, but the level 20 requirement limits its usefulness.
Even if you make everyone in the game hostile, you can still trade with the Vendertron at Gun Runners, so you'll always have a solid source of ammunition and weapons and a place to sell things. It will also carry unique weapons normally sold by other shops if the original shopkeeper is dead.
XP definitely doesn't come as easily in a 'kill everything' run because nothing really gives the amount of XP that quests do, and a lot of the extra NPCs you'll be killing give very little XP and don't respawn. It was years ago that I did a playthrough like this, but I wanna say I killed pretty much everyone in the main game by around level 10 (mostly avoiding caves, vaults, etc). Many enemies will respawn indefinitely, but getting into even the 20s or 30s would likely require a lot of revisiting areas that respawn high-level enemies. I would just plan for a pretty low-level build.
Due to the general lack of XP, Logan's Loophole can be a solid trait option for this kind of playthrough.
Use killall command (big brain)
In regards to the respawning NPCs, I’m still not entirely sure about this, but it seems that disintegrating NPCs will prevent them from respawning as only their ash pile will remain. I think Yes Man may be an exception to this though.
As for an ending, you’re probably going to be siding with Elijah
essentials characters may be killed by selecting them on console and make them normal by commands i guess.
But you gonna feel lonely all by yourself in mohave deserts ;)
Step 1- Use the compliance regulator from HH
Step 2- paralyze with crit
Step 3- Use other gun until enemy dead
Second... Get Holorifle and oneshot everything.
P.S.
Yes-Man can be killed and it will respawn after sometime, though sometimes scripts would be screwed.