"There's a lot at stake because there's a lot of emotions and you're playing for your country," Djokovic said. "You really want to start well and want to bring the first point to Serbia."
Although the 6-foot-9 Isner posted 17 aces, his serve let him down. The 23rd-ranked Isner put only 54 percent of his first serves into play in contrast to Djokovic, who capably put 77 percent in play.
Isner presented Djokovic with four break-point opportunities in the two-hour match and the Serbian made good on all four.
Djokovic had 10 unforced errors to 37 for Isner, which also allowed the Serbian to dominate throughout all but the first few games of the match.
"I think after the first set he became a lot more comfortable," Isner said of Djokovic. "He started playing really well.
Isner was ahead by a service break in the initial stages of the first set, breaking Djokovic in the third game when the Serb hit an unforced forehand error.
"I was a little bit nervous at the start and was being too cautious with my play and not really taking the ball early," Djokovic said. "That resulted with being a break down."
But Isner couldn't hold on to the advantage, surrendering his serve in the sixth game.
Isner had won his five previous tiebreakers in Davis Cup action, but couldn't keep that streak going. Djokovic took advantage of his third set point in the tiebreaker with a forced backhand return error.
"I think I could've served better and I didn't," Isner said. "The mistake on my part is I had to do my best to that little lead I had and I let him back in it.
"To do that against this guy is not a good recipe."
In the second set, Djokovic secured service breaks in the third and seventh games. And in the final set, Djokovic broke Isner's serve in the 11th game. Djokovic won the last 12 points of the match.
"After I got the crucial break (in the first set) then I served really well," Djokovic said. "After that, it was a great performance."
American Sam Querrey took on Viktor Troicki in the second match of the day.