Djokovic is 20-7 all-time in Davis Cup play and was seen as a driving force that boosted Serbia to the 2010 Davis Cup title. That was also the start of the charge Djokovic made to become the No. 1-ranked player in the world.
He was put into the prime position for Serbia for the best-of-five series as he's scheduled to play the first match both Friday and Sunday.
The series is to be played on an indoor hard court in Boise, Idaho, with the winner earning a spot in the semifinal against either Canada or Italy.
Isner, known for his powerful serve and ranked 23rd in the world, is 1-2 lifetime versus Djokovic, winning their most recent meeting about a year ago in three sets. The second match Friday pits 20th-ranked Sam Querrey against No. 44 Viktor Troicki.
Querrey also beat Djokovic last year but will be seeking just his second win in seven matches over Djokovic in the first match Sunday before Troicki and Isner face off in the final match.
Serbia defeated the United States 3-2 in a 2010 first-round match in the only Davis Cup meeting between the countries.