I was reading back on older topics posted when I ran into this one, and sorry I wasn't able to add any comment until now. Really wish I'd caught this one when you first asked, but I believe there's something to the old adage "better late than never."
Part of the overall comfort with your trip will depend on how, and when you intend to get to "Point A," after your departure from Tampa, whether it be driving a rental, flying in, or riding the greydog, or however else may be possible under the circumstances.
Since you're talking about taking east-bound #50, don't exclude Ashland, KY from your list of possibilities. Because of what I've seen so far, this town is on my list of places I'd connect and ride the hound from or to, since the bus station and Amtrak stop are in the same location, and the downtown hotel is a minimal stroll away. Your earlier departure would allow you to follow more of the Ohio river to begin the journey.
Huntington has much to offer with Marshall U. being a driving force of the community, and the previous hotel suggestion is good, and not your only option. I have walked from that area to the Amtrak depot, but I don't recommend the trek for most. A pre-arranged hotel shuttle (if available) or cab would be just fine. The same applies if you're considering a bus, but flying in/out never seemed to be a practical option once considered.
The Amtrak station for Charleston is across the Kanawha river from downtown, and the Holiday Inn I've always stayed at can be eyeballed, but I sure wouldn't consider walking there, or anywhere else from the depot. Forget that it's the capitol of West Virginia, that's another part of town. There's enough to do close by, and the bus station is not far away. If you're flying, the airport is way up on a hill somewhere else!
Since you're taking #50, the main recommendation I'd make is that you get there the day before your departure.