I usually go up through Jonesboro, then Rt 412 to Rt 65. This year I?m driving a 32 ft motorhome with a toad and Ill go over on I 40 to Rt 65. Either way has its drawbacks but there is no good direct route.
Rt 412 is good but you have to pay attention since it makes a few turns that are easy to miss if not paying attention.
I 40 to 65 puts you on more interstate but Rt 65 is hilly with curves (very scenic though). There are many passing lanes. when you get up to Harrison on either route take the left lane through town (even the trucks do) because the lanes are VERY narrow. The center lane gives you some wiggle room. The right lane has a fairly high curb and no wiggle room.
Both are about equal time.
Enjoy the drive