The route would be from Heidelberg down the Neckar river to Mannheim (totally boring part, flat, industrial) and then the Rhine river down to Mainz (also rather boring; only sight: The Worms cathedral and a few vinyards further down the route). From Mainz it would be up the Main river (purely industrial on that stretch; it only starts to get interesting shortly before Frankfurt).
However, from Heidelberg the Neckar up towards Neckargemünd or Neckarsteinach it MOST SCENIC. Plenty of medieval castles and the river is winding up gorge after gorge.
It's easy to book day trips on that stretch, even one-way by boat and back by train.