The NCR, Caesar's Legion, Mr. House, and Yes Man all offer different endings. Your reputation with each faction changes based on your actions throughout the game.
Tag skills that match your playstyle. Speech opens many dialogue options, Guns/ Energy Weapons for combat, and Science/Repair for tech solutions.
Play Dead Money, Honest Hearts, Old World Blues, and Lonesome Road in release order for the best narrative experience.
Start with SPECIAL 5/5/5/5/5/5/7, or push Luck to 9 if you plan to crit-stack with Finesse and Better Criticals. Tag Guns, Speech, and Repair - Repair unlocks Weapon Repair Kits, which keep early guns alive when the Mojave is stingy with caps.
Leave Goodsprings with a Varmint Rifle and dig up the buried supply cache behind the schoolhouse (you need a shovel or the Lucky Shades perk). Primm's sheriff quest hands you a free 9mm and a safehouse; Novac's motel room is the cheapest permanent stash in the game and comes with a bed for the Well Rested XP bonus.
Reputation is tracked separately for the NCR, the Legion, and each minor faction. Wear a disguise before entering a camp you have already raided - the disguise resets hostility but not your reputation. Killing named Legion officers during Render Unto Caesar locks you out of the Legion ending permanently.
For House, complete The House Always Wins through part IV before level 15 so you keep the Lucky 38 penthouse and the casino floor. Yes Man is the fallback: his quests never lock, which makes him the safe choice if you want every ending open until the last act.
DLC order matters less than level order: hit Old World Blues around level 15 for Implant GRX and the Sink auto-docs, then Lonesome Road at 25+ for Ulysses' dialogue checks.
Boone's spotter perk marks targets through walls, and ED-E's repair perk keeps your gear at full condition in the field - both are worth picking up before level ten.