If you stop overnight, make sure your hotel has a functioning indoor pool, and no matter how tired you are, take him swimming that night and again in the morning before you leave the hotel. He will probably have been sleeping in the car for a long time when you arrive, without exercise he will want to bounce around all night. The point of swimming again in the morning is to wear him out so that he will sleep in the car again! Swimming is one of those exercises that is good for getting the kinks out and invigorating adults, but I find that it really wipes out little kids.
Also, check around on the web for information about playgrounds in towns along your route. Print out the directions, and take the time to get off the highway and get to them. If it is deep winter, find out about indoor play areas, shopping malls, etc.; you'll want places where you can let him run. (Yes, there are the play areas in fast food restaurants, and those will do, too, if you don't mind that sort of food. We find that starchy fast food makes us too easily sleepy when driving.)