Zverev was on the receiving end of a Novak Djokovic masterclass on Wednesday as he lost 6-4, 6-1 but his opening win against Marin Cilic puts him in a strong position to qualify for the knockout stages.
A win against Isner would effectively guarantee him qualification to the semi-finals so he has it all to play for in this final group stage match. The only black mark against him at the moment is that in the aftermath of this defeat to Djokovic he revealed that he has been struggling from fatigue.
The German has had Isner's number in the past having won four of their five career meetings and his game matches up well to the big-serving American.
Isner's serve surprisingly let him down against Marin Cilic on Wednesday as he was broken numerous times on his way to a 6-7, 6-3, 6-4 loss to the Croat.
That defeat - coupled with his loss to Novak Djokovic on Monday - means that his chances of progressing are all but over, although there remains a slim mathematical chance of advancing to the semi-finals.
The American will want to end his season on a high and did actually beat Zverev in the final of the Miami Masters earlier this year, but he is currently playing nowhere near the levels he was on the sunshine stretch so he will need to turn his form around if he is to stand any chance.
Zverev will not be too disheartened by his loss to Djokovic on Wednesday as before the tournament he will have been targeting wins against Cilic and Isner. Having already defeated the Croat on Monday, Zverev will now look to complete the second half of that double and he has certainly been playing to a higher level than Isner has in London, despite his troubles with fatigue after a long season. The American struggled with his return games in his first two matches and his usually formidable serve has also let him down at times, so there only looks like being one winner here. Zverev in straight sets.