Which route to take...reminds me of the old joke about which method of execution you would like - gas chamber or electric chair. No matter which way you slice it, it's a bit of a drive from where you are; I guess the key question is how much traffic do you wish to avoid? Cherokee isn't that bad, but Gatlinburg in high summer, as you know, is horrible - it has taken me 30 minutes to get through it at times. As long as the Blue Ridge Parkway is open, you can get on 441 briefly, then get on it and cut over to Maggie Valley, then go through it to 276 to I-40...I would probably recommend that, even if it is longer, mileage-wise. Once you get on I-40, it's less than 30 minutes to get there.
Because it involves a drive, no matter where you are in the park, I'm not too worried about Cosby being over-fished. I've hardly run into anyone else fishing there when I was there. If you go during a weekday, I can almost assure you that you'll have the stream to yourself...now, the hikers are another story....they kind of look at you wierd if they see a flyrod in your hand instead of hiking poles