If you were doing MLB, NHL, or NBA you could do the travelling salesman problem.
But in the NFL the teams return home after every away game. Now you would minimize travel costs in the NFL if you scheduled each team 8 consecutive home games but that would be aesthetically displeasing.
One thing you might look at in the NFL is the assignment of primary and secondary TV markets. You can easily see the flaws in this analysis:
I suppose you could argue some of these are tertiary markets:
Looking at assignment of divisions would be trickier - it's hard to quantify the value of preserving certain rivalries.