Between the Highlander's three powertrains, there's a pretty wide range if you go by the EPA ratings; but in real-world testing, as we've seen it, much of that difference is erased.
With its base four-cylinder engine and front-wheel drive, the Highlander rates at 20/25 mpg in EPA tests. Mileage drops to 18/24 mpg with the V-6, and goes down to 17/22 with all-wheel drive. That's about on par with the Ford Flex.
The Highlander Hybrid is really the green star of this lineup, with ratings of 28 mpg city, 28 highway, along with quicker acceleration than the base model. But in real-world testing we've never managed to replicate those numbers; over several drives we've seen a bit lower.