Not everything is worth picking up
You might be tempted to pick up every weapon you find. Don't. Figure out what you want to use and get like items to repair it. If you use a 9mm pistol, you don't need to pick up .44's and shotguns. Pick up 9mm pistols and use them to repair your main weapon.
Weapon mods (especially when playing Gun Runners Arsenal) are also good investments.
Pick everything up
Early on, you need to grab as much as you can carry and sell it off. A good technique is to empty Goodsprings in waves and sell everything off. Take a few days between shopping trips to let the general store restock on caps. Don't let the game rush you. The wasteland isn't going anywhere.
Sell off high value DLC items that you don't plan on using, or stick them in storage (easy when you get a place in Novac) and sell them off later. I hate that you can't get a place early on, and that you have to wander halfway across the Mojave to find a home base. Bad design.
When you do get a place in Novac, it opens the game up.
Know your Weapons
The best thing you can do is learn how your weapon works. What is the strength requirement, what is the spread, how many action points does it use in VATS, and what type of ammo do you need? Make sure you know if it is a unique item or a common one, know what perks work with it. Make sure you have compatible mods for the weapon.
This might all seem like pointless stuff to learn, but it makes a difference. When you have a sense of what you can do with a weapon, it means you have less incentive to mindlessly pick up everything you see. You'll also know what ammo is worth carrying and what you can scrap or sell freely.
It makes playing the game easier, and makes a massive difference in Hardcore mode.
Pay attention to your relationships
Some factions grant bonuses in certain areas, and some are purely novelties. Being a Follower of the Apocalypse couples very well with being friendly with the Brotherhood of Steel, to an extent.
You need to pay attention to the endgames of these factions too. There isn't a happy way to reconcile working for the NCR and the Legion unless you are vying to tear it all down. The fun aspect of this game is the complexity it offers, and knowing your friends and enemies is just a facet of that.
Pay attention to your build
You don't need to waste a perk on something like Educated for instance. You will get more than enough skill points to max out a combat skill, a defense skill and a utility skill. Wasting a perk to get two more skill points is senseless in the long run, especially when you consider how common skill magazines and stat boosting gear is.
Carrying a few weightless magazines that will give you a temporary 10 point skill boost makes more sense, trust me.
Do what is fun for you
Wanna be a pink haired grenade tossing chem taking psycho with a soft spot for Raiders? Go for it. Wanna be a one person wrecking crew killing any and everything that looks at you funny? Do it.
Have fun with this game, in the end that is what it is for.
Thanks for reading, see you next time.