Fallout: New Vegas

TL;DR

Default difficulty is fine for casual players. Hardcore is bad if you're using companions and not modding the game.

INT is good. All weapon types are viable mains. Lockpick, Medical, Repair, and Science are good. Hauler is good.

Play the DLC in release order (Dead Money, Honest Hearts, Old World Blues and then Lonesome Road) starting at about level 20, then gain 5-10 more levels before moving onto the next.

If you're modding, get a UI fixer (MTUI), New Vegas Script Extender (NVSE), an unofficial bugfix patch (YUP or UPP+), and the Fallout Mod Manager (FOMM). Don't add anything else unless you want something specific, and add them one at a time.

Don't neglect Strength (carry load), Endurance (max HP), and Intelligence (skill points per level.) Charisma is a safe dumpstat. High Luck can make for easy money grinding at casinos, but if that doesn't interest you then it is also a safe dumpstat.

Don't put anything to 10, there are implants that can permanently upgrade stats, and the max is 10 even with buffs/chems/etc.

If you have an Intelligence of 2 or 1, the game changes in some pretty significant ways, but this is better suited for a second run than a first.

A high Charisma/nonviolent character is also viable, but also better saved for when you know what you're getting into.

Wild Wasteland is serious about making the game sillier, including most of the shout-outs and goofy events/locations. Everything else depends on your build, but if you can't decide, Hoarder (from the DLC) is excellent and the downside is extremely easy to avoid.

Don't play on Hardcore if you plan on using companions and not modding the game. Their AI is questionable and there are several bugs that can kill them dead with very little recourse, especially melee companions, and especially especially the good, good robot dog.

For combat skills, pick one and go all-in. Whether it's Melee, Unarmed, Guns, Energy Weapons, or Explosives, pick one, and pick out perks that support it and work well with it. It doesn't hurt to be putting points into a secondary weapon type, but focus your combat perks on whatever you intend to be best at. (Do note that some of the best Melee perks require Unarmed skill, and vice-versa.) Explosives are a bit expensive to be a main if you don't know what you're doing, but exploring the right areas can take some of the edge off.

Survival is a garbage skill that does nothing of value, even in Hardcore mode. Most of what you'd want it to do is actually behind Medical, Science, or Repair.

Speech and Barter can be worth putting a few points into even if you don't lean into them. If you're just shy of making a check, fancy clothes, a magazine and chems/alcohol can close the gap.

Make sure to level at least one of Lockpick and Science, most good loot is locked behind one or both of them.

Perks that increase skill point gain are not retroactive, so take them early. Avoid XP-boosting perks, there is more than enough to comfortably hit the level cap with even a modicum of exploration.

There are no missables, although you can't do everything in one playthrough. There is no way to totally fail most quests (except contradictory ones from different people - kill this guy vs rescue this guy) so pick a character archetype to roleplay and just do it. You might "fail" some quests but you really won't.

Much like Fallout 3, if a container isn't "secure" then the game may or may not remember what you stored in it. Containers in your personal houses and rooms are secure, containers elsewhere generally aren't. The first accessible ones are the blue Mohave Express drop boxes, which will freely hold and transfer an infinite amount of stuff between them once you find two or more. (There are five, one each in Goodsprings, Primm, Novac, Freeside, and the Strip.)

Karma is basically a nonissue, it's faction reputation that's important. The only companion (and really the only NPC) who cares about Karma is Cass, who'll leave if it's too low for too long, but several care about faction reputation.

If you are wearing a faction's armor, people will think you are a member of that faction. For example, you will be attacked if you return to Goodsprings wearing Powder Ganger armor.

At a certain point in the main plot, there's a one-time event where negative reputation with the NCR and the Legion will be cleared. Outside of this, there isn't really an easy way to repair your reputation with a faction once they start getting violent.

Run from Cazadores until you get lots of poison antidotes or have done the Old World Blues DLC. The poison is bugged and can infinitely stack every time they hit you. This is also one of the fore-mentioned enemies that can kill companions dead extremely quickly.

Armor uses Damage Threshold (which subtracts points of damage off the top) now instead of Damage Resistance (which reduced all damage by a percentage). This makes Deathclaws even deadlier than before, if you can believe it. Use AP ammo on them, preferably from an extreme distance. There's no Dart Gun equivalent to neuter them anymore, either.

Wanna just play the game for the story and absolutely roll over everything even remotely challenging? Or, alternatively, wanna stand a fighting chance at max difficulty? This is how. Mechanical and location spoilers follow.

5 STR, 8 PER, 7 END, 1 CHA, 9 INT, 5 AGI, 7 LUC. Tag Energy Weapons, Repair, and Science. Take Hoarder and Wild Wasteland.

Key perks early/mid perks are Educated, Comprehension, Toughness, Meltdown, Vigilant Recycler, and Jury Rigging.

Make Overcharged and Maximum energy cells at repair benches once you have Jury Rigging to easily repair the damage to your weapons.

The Plasma Caster is the best all-round energy weapon in terms of damage, fire rate and ammo usage. You'll find it in the Silver Rush in New Vegas. Steal it or kill everyone inside.

Northwest of the strip is a little town called the Horowitz farmstead. Just north of that is an extremely deadly Wild Wasteland-specific unique energy weapon, wielded by a unique enemy. Use the ammo carefully, you're not getting any more of it.

Play through the DLC in release order, so Dead Money, Honest Hearts, Old World Blues and then Lonesome Road. They're individual side stories but each one also contains buildup for the last one and they're all pretty awesome in their own ways. Dead Money recommends level 20 or higher, but it can be done at as low as 10-15 if you're a combat monster. It does have some high Speech and Lockpick checks, so pump those skills first if you plan to go in early.

Before even starting the game, if you're on PC, you're going to want a UI fixer (MTUI), the New Vegas Script Extender (NVSE), New Vegas Anti-Crash (NVAC), an unofficial bugfix patch (YUP or UPP+), and the Fallout Mod Manager (FOMM). These can be added quickly and painlessly even if you don't want to mess around with modding.

If you want to mod more, add one at a time, make sure it works, and unless all of the mods you're using are explicitly compatible, be prepared for some odd crashes and fiddling with load order. Good places to start are Project Nevada, Weapon Mods Expanded, and The Someguyseries (New Vegas Bounties, et al.) for gameplay, and Fellout, Interior Lighting Overhaul, Fallout Character Overhaul, and one of the several texture replacement mods for visuals.