If there’s anything you can count on, it’s your players coming up with the most random, bizarre questions and courses of action.
The single most helpful thing I’ve found so far to deal with both the questions and random directions is to ask myself “why?”
Not “why are the players doing this or saying this?” but “why are my NPCs (both allies & villains) doing and saying what they are?”
Once you have your NPCs motivations down, the rest is easy to make up on the fly.
Now get out there and tell a story!