Both players have moved through the first two rounds with peak efficiency as Mertens defeated British wild card Harriet Dart 6-1, 6-3 in the first round and Lin Zhu 6-2, 6-0 in the second round.
Likewise, Keys also started with a British wild card, knocking off Katie Swan 6-3, 6-4 before a 6-1, 6-4 second-round victory over Lauren Davis.
Keys leads the head-to-head 2-0, having previously defeated Mertens in the first round of the 2017 Australian Open and third round of the 2019 U.S. Open.
This will be the third match on No. 1 Court with the winner advancing to the Round of 16 against either Viktorija Golubic or Madison Brengle.
This is a clear contrast in styles as Keys will want to use her tremendous power on her serve and groundstrokes to dictate play while Mertens will turn to her movement and solid baseline game to find success.
The length of rallies will be important as longer points favor the Belgian while shorter points will give the American the advantage.
The Mertens backhand is going to be a key shot as she can use it to win points anywhere on the court, especially crosscourt. It's imperative Keys stay neutral on that wing and impose her forehand, where she has a clear edge.
The American will also want to pick on the Mertens forehand and second serve, neither which is an especially effective shot. Consistency, which is a strength of the Belgian, will also play a factor.
These are the matches you like to see in the middle stages of a major: two seeded players who play different styles that are evenly matched.
Both players have hardly been challenged so far and are taking several steps up in class. Keys is the one who can sometimes go off the rails and commit a bunch of unforced errors while Mertens can be overpowered.
This will be a back-and-forth match with lots of twists and turns and in some ways, it's a shame they have to meet this early. Expect Keys to win a very tight encounter.
Prediction: Madison Keys in three sets