Imagine you are going from point A to B with 2 routes to pick from. Route X is 50 miles and you can get 50 MPG. Route Y is 60 miles but you can get 57 MPG.
What route should you take?
Route X will cost 1.00 gallon of fuel.
Route Y will cost 1.05 gallons of fuel.
Even if you care about fuel efficiency above all else, MPG is just a vague number that should be taken with a grain of salt. It is only useful as an absolute statistic if you are driving on a set route.
Other than total fuel cost, factors that people may want to consider include: time, vehicle wear, mental health, scenery, etc. The best thing you can hope to do is weigh the factors and make an intuitive guess on the best route. MPG should not be the primary goal unless you're some sort of whacko.
Something I often have to face is driving through the city, or taking a highway that goes around the city. I know that MPG will probably be better on the highway, but straight through the city is a much shorter route, so total fuel cost will be cheaper that way. However the city also takes 20 min longer (if I'm going all the way across) and has some annoyances of city driving. In the end this decision however comes down to TIME. If I'm being paid by employer, I'll go through the city to save fuel cost (I don't get paid fuel) and maybe even to burn some extra time.
If I'm on my own time I'll usually go on the highway because it saves time and gives me more peace of mind. Maybe there is more I should consider, I'm not entirely sure that was just my best guess so far.