The route you chose from Lexington to Moundsville is definitely the easiest. Once you get off of Interstate 64, the roads smooth out and by the time you get on WV 2 from Parkersburg to Wheeling, you'll think you are in a different state because the road is beside the Ohio River and is flat.
I've been to the Wheeling Island Casino many times, and have really enjoyed it. The casino is nice and very festive. However, I have never stayed in the hotel. Wheeling is known for their Italian food, so you may want to explore a few restaurants there (Bella Via, Undo's, Figaretti's).
Downtown Wheeling is small, and just across the river from the Casino. There is a historic old hotel downtown that you may want to look into: http://www.mclurehotelwheeling.com/
Your route back to Weston is definitely the easiest, being all interstate driving. I'll assume that your tour to Moundsville and Weston are to visit the old Prison and the old Asylum. Sounds like a paranormal exploration! If so, have fun. Both are very interesting and worth the money for the tours.
As for the Mystery Hole, it is about as tacky as you can get. I love it! But, it is definitely not a "must see." And the road to get there (route 60) is very scenic, but VERY twisty. If you aren't used to mountain roads, it would be an adventure for you! If you decide to go to the Mystery Hole, then be sure to stop at Hawks Nest State Park for the incredible view.
Have a great trip. Please feel free to toss out any questions you may have.
Edited: 7:49 am, August 29, 2013