Save your bullets and carry a variety of weapons
One of the things that makes Fallout so challenging is that ammo is a precious resource in the wasteland, which should give you pause when you want to start spraying bullets willy-nilly at a pack of raiders. Diligent scavenging can help alleviate this, but there’s no guarantee you’ll find the particular type you need, and rarer calibers can be expensive to buy. Always carry a selection of weapons that use different types of ammo, so you have something to work with if you run out of one kind or other. As the game goes on and you run into synths regularly, fusion cells in particular will be plentiful.
As a last resort it’s also always good to have a melee weapon with you. Grognak’s Axe is one of the best in the game, and is easy enough to snag from the ground floor of Hubris Comics near Diamond City. Come in prepared to fight a room full of feral ghouls and then you can pick it from the case behind the counter. If you haven’t found it yet, the Silver Shroud quest from Goodneighbor will lead you there.
Save early, save often
Fallout can be a punishing game at times, so expect to die a fair amount, especially early in the game when you’re more likely to wander into someplace for which you are not at all prepared. It can be extremely frustrating to make your way through most of a building, fighting everyone and meticulously checking every drawer, only to lose focus for a second and die, having to go back and repeat the whole thing. Bethesda games also have a reputation for being a bit buggy. Our experience of Fallout 4 has not been so bad, but it did crash twice in about 40 hours. The quicksave feature is there for a reason, so it’s a useful habit to utilize it regularly.
Let enemies bring the fight to you
If you’re having a hard time with a particularly challenging fight, fall back to a position you can better defend and let enemies come to you. Enemy AI is not stellar, so you can usually just backtrack through a door and wait for them to follow you, one or two at a time, and blow their heads off with a well-timed VATS shot.
Relish the little things, and explore
You could plow straight through the main story in about 20 hours if you really set your mind to it, but what would be the fun in that? The story is fine — better than Fallout 3 to be sure — but isn’t really the main selling point. Fallout is a game for luxuriating in, so relax, explore. Many of the best moments in any given Fallout game aren’t major plot points, but rather are the side quests and the strange little bits of environmental storytelling found throughout the game in tableaus and terminal message logs. Take your time and enjoy all the meticulous detail and exquisite world-building that you will find off the beaten path.