I flew with my DS 3 and DD 1 cross-country by myself just two weeks ago. We are frequent fliers, and I feel confident in my abilities to keep my children entertained and in good form on flights. But that said, they are still kids, and since I as flying by myself I spoke with our pediatrician about Benadryl for my DD. (My DS has a DVD player, and we brought crafts, coloring books, playdough, etc. for him - he was awesome.)
But my DD is at the absolute worst age to fly with. She's been walking for months, can't communicate, doesn't understand consequences and isn't easily entertained in a seated position. Since I was by myself, I decided to try the Benadryl. When we did the trial run the week before the trip, it worked like a charm. But just as a PP noted, when I used it on the plane it didn't work as well. She slept for an hour, but when we awoke she was NOT happy. Then I was dealing with a ticked off, tired, groggy, freaked out toddler, rather than just a busy one.
Since you are traveling through the night, would it be too much to hope that your little one would sleep on his/her own? You might be surprised. Once the initial curiosity wears off, sleep might come on its own. Just a thought. But do what you think is going to give you the best shot at arriving with your sanity intact, your children in good spirits, and other passengers not throwing tomatos at you.
If you do decide to try Benadryl, don't beat yourself up about it. And don't worry about what others might think. People who drive to their distination have the luxury of stopping whenever they need to, getting out the of car, and walking around. Their kids can burn off some steam. Airplanes don't offer that luxury. And when you drive, if your kids are nutty, there's nobody to be bothered but yourselves. On an airplane, you are also trying to be considerate of hundreds of other travelers. Don't sweat it - do what you think is right for you.
Good luck!!!