You'll certainly find it technically outdated and it'll take you some time to get used to the interface. I remember very well a friend who had some serious troubles to use it. The main hint is: use the right-click on anything to see what you can do with it. Actually, the left click is almost only used to go somewhere. The icons which will appear in the contextual menu should be quite self-explanatory. Gameplay wise, you'll discover the turn-based combat system and you will probably go in the options right away to max the speed you'll see your enemies playing their turn. You'll also probably want to turn on the "always run" option.
Another great difference you'll see is that the gaming system is far more balanced than the Fallout 3's one. You'll be able to have at most 2 skill at 150% + (but if it is a ranged weapon one, you'll also end up with a permanent 95% hit anywhere at any distance) and you'll have an hard time to get more than 5-6 skills in the 100% range. That because skill can go up to 300% but you'll have to spend more skill points to get past 100%. It'll goes from 2 points per 1% boost to 6 points which make going higher than 150 pretty expensive and useless. The tag skills are different: you won't get any boost but each time you'll spend skill points on these skills, you'll have a 2% increase instead of 1 so it goes up twice faster.
It will also be far more harder to boost your SPECIAL attributes and the perks will be given far less often, ie only every 3 or 4 level. Another major change is that on character creation, you'll be able to chose up to 2 traits which are roughly some initial and very powerful perks which will
always have a downside. For example, the Night Person trait enhance your intelligence and perception at night but it's equally decreased during day. The sole exception is Bloody Mess which does only add some gore effects when enemies die but does not increase your damage at all.
In the end, you'll have a far more specialised character and following your attributes and skill choices, some very different experiences.