I think we had a thread about this a couple of years ago, and my suggesting was the same: Please do NOT change anything. But IF you are, give this a shot...
First off, increase the roster limits and ditch the IR = Season Over rule, make it more like baseball with the different limits (15 day, ect). If there are going to be more players needed, it would be better for them to learn the system they are playing in than getting signed off the street Tuesday and playing Sunday. That leads to poor football which leads to more injuries and by the end of the season they will be holding open tryouts for the fans at the game that day.
Give each team 2 bye weeks. And to make it fair (although I doubt the league would go for it) everyone's bye should be the same. Play 6 weeks of football, bye, six weeks, bye, and then finish the season. I know a Sunday without football would suck, but they aren't robots. We'll manage. Or, just have 30 team off on the bye and have a Sunday Night Special that week, then give those two team off the next week. Maybe one Sunday Nighter is an AFC Championship Rematch and the other is an NFC Rematch. Thanksgiving could stay the way it is. Have divisional games in the first 3rd and last 3rd of the season, not the middle. It looks like the league is going this way, anyways.
And finally, knock the international crap off. I don't want to see a game in London (Super Bowl included), China, Germany, Brazil, or Japan. Mexico City and certain parts of Canada are ok, if they care (I don't remember how the Mexico game went, but we haven't had one there since so...). But if Europe or Asia were really into it, they would start a league like the US did with MLS. I understand there is an audience for American Football in these places, but it isn't anything like the mania we have here in the States. Reopen NFL Europe or something...even more wear on the players bodies from the flying and time zone adjustments, plus the 2 extra regular season games is not cool.