Isner saved six break points to force the early tiebreaker and took the first set when Djokovic's backhand sailed wide.
The second-seeded Serb raised his game in the second set, making only two unforced errors and breaking Isner twice.
Djokovic then won the last five games of the match, finishing off Isner with a backhand volley.
The Australian Open champion next plays Stanislas Wawrinka, who stayed in contention for one of the two remaining ATP finals spots by beating Nicolas Almagro of Spain 6-3, 6-2.
The seventh-seeded Swiss rallied from a 3-1 deficit in the first set and broke Almagro twice in the second.
Defending champion David Ferrer also advanced, beating Gilles Simon of France 6-2, 6-3.
Milos Raonic of Thornhill, Ont., was scheduled to play his third-round match against Tomas Berdych of the Czech Republic later in the day.