The best I have seen are, unfortunately, not D&D settings.
1) Classic Deadlands. The books are *loaded* with sandboxy ideads and hooks. As someone who was running the game, but not following the canonical campaign arc (because, while most of the adventures in it are okay, the end of it is a craptastic railroad into a brick wall of an NPC the players cannot beat), the setting material has more adventure hooks and plot ideas than you can shake a dead jackalope at. The players are goig somewhere? Okay, open the book, and read the dozen or so different tthings going on there, and riff on it. Easy as pie.
2) Original Alternity - Dark Matter setting. Possibly the best setting book ever written, in terms of its content of seed ideas. Great if you are running an X-files game, not so hot if you are Thork the Barbarian.