I particularly like the Fontana area -- working my way northeast in the park.
One very fun loop that I did over July 4 weekend started at the Twentymile Ranger Station.
Twentymile Trail (easy creek access the whole way) to the beautiful backcountry #90 site. From there, go up Eagle Creek Trail (tons of fun stream crossings followed by a steep ascent to Russell Field) all the way up to the AT. From the AT, work your way back west on the Gregory Bald trail, and then take Wolf Ridge Trail at BC #13 south back to Twentymile.
If I recall, the total was around 35 miles, but if you extended the loop in to the Cades Cove area, you would probably cover about 55-60 miles.
If you don't want to go that far west, then you can never go wrong with the Big Creek area. One problem with Big Creek, however, is that it may be a little more difficult to make a loop without extended overlap.
Site reservations should be no problem over Thanksgiving weekend; but when I went in mid-September many sites throughout the park were closed because of bear activity. From my experience last year, bears are still very active through December, so be sure you call before you go.
Generally, temperatures are really not that bad until mid-January. You should be able to get away with just baselayer insulation, midlayers, and rain/wind protection and be able to leave the insulating outer-/sleep-wear at home.
One thing worth noting is that the springs have been very dry on the west side of the park this year. If you elect to hike on the west side, then try to follow a creek and camel up for the ascents.