I have five kids and have lived cross country from my family for years. We have traveled back and forth several times, and I usually make half the trip without my husband who has to return sooner than the rest of us for work.
I have a sixteen month old little girl (my youngest). It is a difficult age to travel with, especially boys who always seem to have a neverending source of energy.
First of all, in my experience, giving Benadryl is a bad idea. I tried it once with my oldest when he was about four on a three hour flight from Texas to Utah. I had a newborn, also. He freaked out--not quite awake, not quite asleep. It was awful.
The thing I do when I travel (and it seems to work really well) is to bring realistic (and lightweight) entertainment for the kids. For my girls it is usually small dolls (like Polly Pockets) they can dress up or coloring books. Now that they are older, we take a portable DVD player and they watch movies. (We have a couple so that my now 3-year-old can watch his own.) My 16-month-old, though, would never watch a movie. She is not interested at all. For her, I take snacks, books, and her blankie. She likes to look at books. We also have a set of finger puppets that she likes to play with.
It is hard to travel with a toddler, but not impossible. I remind myself before every trip that if we are to get through the trip unscathed (and without bothering all the people seated around us) that I will have to stay on top of all that my children are doing. I never try to read or rest because someone always needs something (there are five of them...six if you include my husband). I do take a magazine or book just in case they all fall asleep, although I think this has NEVER happened.
You know your child best and what he enjoys doing, so bring activities you know he can sit and do. I don't know which airline you are flying on. There are good ones and bad ones. The best one we've flown on with kids is Southwest.
One more thing--make sure to bring an empty sippy cup and have the flight attendant bring you water or milk or something to put in it when you get on the plane. (You can't bring any liquids on board because of the new flight restrictions.) I have had some children who have a very difficult time with takeoffs and landings because of the change in air pressure. Sometimes having a snack helps them swallow and pop their ears.