Djokovic's return to the top of men's tennis has been sensational and he is clearly the man to beat in London. Since losing in the French Open quarter-finals in June, the Serb was victorious at both Wimbledon and the US Open and completed the Career Golden Slam of Masters 1000 events by picking up the Cincinnati title.
The new world number one is seeking a record-equalling sixth World Tour Finals title and few would bet against him doing so to round off a breathtaking second half of the year.
Djokovic's 22-match unbeaten run finally came to end in the recent Paris Masters final when he ran into an inspired Karen Khachanov but he was physically drained after gruelling deciding set wins in the previous two rounds.
Isner makes his debut at the event as a late stand-in following Rafael Nadal's withdrawal and will open his account by facing up against Djokovic for the first time since 2015.
The American's most recent result was a Round of 16 defeat to eventual champion Karen Khachanov in Paris in what was an extremely tight match decided on a tie-break.
Isner may draw belief from Khachanov's victory over Djokovic in Paris as he has a somewhat similar game to the Russian youngster, with a huge serve backed up by a dominant forehand.
Djokovic has largely been invincible in recent months and it is difficult to look past him winning the whole tournament, let alone this opener against an opponent he has beaten eight times in ten matches.
The slight blip in Djokovic's recent résumé is his loss to Khachanov in Paris and Isner will try to use the Russian's performance as a template for success, but in all likelihood that was a momentary lapse in Djokovic's meteoric return to the top of the game and he should be equal to anything Isner can throw at him here.
Isner's huge serve will keep him interested throughout and he is capable of making this is a close contest, but Djokovic's level of play and self-belief make him a huge favourite here and he should get off to a winning start. Djokovic in straight sets.