New Vegas has a few mechanical tweaks over the Fallout 3 base (like the hardcoe mode which compiles some specific gameplay features, and skills and SPECIAL having far more uses than in the previous game), and then there's a completely different and much more hands-on narrative. The storytelling element is the biggest difference between the games. In New Vegas things add up, you get to make choices and they will have consequences (some more far reaching than others). Without spoiling too much; along with a plethora of multi-choice sidequests (some of which tie in with the MQ in one way or another), you have a four-way main quest (four paths that exclude each other out) and you are very free to pursue them as you wish. All paths having their own reasonings and leading to unique outcomes in the end.
That's it in a nutshell and without spoilers.
What was your favorite TES?
If it was Morrowind, I reckon you'll enjoy NV.