Necessary to make reservations for hotels in Provence in October?

The only crazy part would be staying in Orange, in my view. If you are flexible I think you can travel this way without worries. That means you are okay if you don't get a particular hotel or even a particular locale. (Remember, smaller towns often means fewer rooms.) I think the smartest way to do this is to call ahead the morning of. Then you at least know where you are going. But I think you can get by. However: With 4 days in Provence, I would not want to spend my time packing and unpacking. Rather I'd pick a base that was convenient to all the places I want to visit during the day and stay put for all my nights. And if you do that, why not reserve in advance? Just one less thing to worry about on the ground. The only argument against is if you might not arrive on the 8th because you might change you itinerary on the ground based on weather or other considerations.

I agree with Adam - I'd pick one place as a base (like St. Remy) and reserve for at least 2 nights. If you really like it, you could extend your stay. If not, move on to another location for the last two nights.

I've only been to Provence once and didn't have a car, so I focused on more "urban" destinations there. So, I can't help with hotel reservation advice. But I do agree about Orange. The Roman Theatre was amazing, with its huge and intact theatrical wall. And while one poster here says he could tell from the outside that the inside wouldn't be worthwhile, that's the point: you have to pay to get in to see anything impressive (they've close off all the free viewing points, so you don't see anything good without paying). But, the town of Orange is dull and a bit grungy, and not of interest except for the theater. Nimes, on the other hand, was a lovely town, with multiple interesting sights and a nice vibe just to stroll around in. I liked it even more than Arles, which I also enjoyed. But with a car, you'll want to focus on smaller towns and rural areas that I couldn't get to.