The large population is easy enough to manage. Just split us into factions, instead of playing as a vault dweller.
Raider
NCR
Tribal
NCR gets the Boneyard, Tribals get Arroyo, Raiders get New Reno. Areas are divided like TESO, but you're free to enter another faction's land, as long as you avoid the capital city.
There would still be loot everywhere, but multiple people can grab the same loot. Certain areas can only be entered alone, or with an organized party, for when they need to build tension (ruin full of ghouls), certain quests are for certain factions only, etc. It's plenty doable.
I'm aware that tribals can freely enter the Boneyard (I think I'm the only one here who knows Fallout/Fallout 2 lore, actually), but this is a gameplay-trumps-lore scenario.