That eventually wore him out and led to mistakes, and del Potro lost 6-3, 7-6 (4), 6-3 on Sunday in the final of the U.S. Open, the tournament he most wants to win again.
Clearly Djokovic will have to neutralise the 6'6" Argentine's blistering serve at the Arthur Ashe Stadium: "Del Potro fired 68 aces during the tournament, winning 82 percent of his first serve points.
But with a third US Open title to go with the Wimbledon crown he secured in July he has matched American Pete Sampras on 14 Grand Slam titles and there is little doubt that the 31-year-old is one of the sport's greats.
Djokovic has won 13 of his 14 Grand Slam titles since 2010, when the prize money for the champion moved past the £1m mark at all four majors.
But del Potro can take heart in appearing in a first major final since 2009, when he upset Federer in five sets.
He was soon 3-1 up in the second set before Potro carved out his first break point of the match to level at 3-3.
But in that critical eight deuce game, the three break chances evaporated.
He needed his right knee strapped after the seventh game before gallantly fighting off two set points in the 10th game, breaking Del Potro who was serving for the set.
Del Potro put up as strong as a fight as you'll see in a straight-set win, but it was Djokovic's day.More news: California locked in to carbon-free power by 2045
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Early in the tournament the extreme heat and humid conditions in NY were clearly troubling Djokovic.
It's clear Djokovic is already one of tennis' all-time greats, but the question now, as it has been for years, is how much more ground he can make up on Federer and Nadal in the Slams race. In terms of results, I played finals of Queen's, won Wimbledon, won Cincinnati and won US Open.
While the scoreline suggested a comfortable evening for Djokovic, the Serbian was still made to work hard and had to produce some of his best and most consistent tennis.
Naomi Osaka on Monday jumped 12 places to No. 7 in the latest WTA rankings following her historic U.S. Open victory, becoming the highest-ranked Japanese woman since Kimiko Date reached No. 4 in 1995. "I'm very motivated to keep trying to win these titles".
Thereafter, there were two service holds and the set was poised at 3-2 and suddenly, Flushing Meadows saw a massive momentum shift. I had my opportunities during the second and third set but I was playing nearly at the limit all the time ... and I couldn't make it because Novak was there every time.
Osaka's moment of glory may have been taken away from her, she could end up having the last laugh at the bank.
Former French Open and Australian Open champion Li Na has been credited with sparking a tennis revolution in China, and Wang said: "I watch some matches about Li Na".
The 20-year-old won 73% of the points on her first serve, while Williams took 63%.
There may have been no game more important to Djokovic's win or simply entertaining than the eighth game of the second set.