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I would take the route that gets you to where you want to be the quickest.
That said, the only reason the Prius has a better city EPA rating is because the speeds are lower than those on the highway. If you drove slowly on the highway, then that rating would be higher since there is less stopping. Stopping is detrimental to fuel economy regardless of what powers the car.
Lastly, fuel economy (MPG) is not important. Amount of fuel consumed to get to your destination is the important factor. If you could take a 10 mile route that gets you 50mpg, or a 5 mile route that gets you 40mpg, it would still be better to take the 5 mile route. What I'm saying is that you need to zero your fuel use gauge (you do have a SG, right?) and drive both routes several times to see how the average fuel consumption compares.
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