Del Potro suffered more heartbreak after losing to Nadal in the semifinals at Roland Garros last month, his 52 unforced errors proving to be costly as the Spaniard claimed the only break in a pulsating final set.
Nadal is similarly battle-hardened after outlasting Juan Martín del Potro in the best match of the men's draw so far, a judgment handed down from the BBC commentary box by Andy Murray.
Del Potro was in danger of being dragged into a fifth set when he squandered four match points, one with a double-fault, at 5-4 having hit back from 1-3 down.
Nadal, 32, and Djokovic, 31, meet in a highly anticipated Wimbledon semi-final at about 16:30 BST on Friday.
"I will try to hold my service games most of the time".More news: Mandzukic sends Croatia to first World Cup final
"It is always a big challenge to face Novak".
He eventually he clinched a 7-5 6-7 (7-9) 4-6 6-4 6-4 victory after four hours and 47 minutes.
After South African Kevin Anderson's shock Wimbledon win over defending champion Roger Federer on Wednesday, one restaurant chain has noticed a unique public relations opportunity. His US Open win previous year was the first time he had won a Grand Slam outside of the French Open since winning the US Open in 2013.
His confidence buoyed, Isner overwhelmed Milos Raonic on Wednesday to reach his maiden grand-slam semi-final. You know that you can not win against Novak if you don't play well. Playing Djokovic was the sternest test and he came through a dramatic five-setter dubbed the greatest clay-court match of all-time by Bjorn Borg and John McEnroe.
The eighth-seeded Anderson stands 6-foot-8 (2.03m), while ninth-seed Isner is two inches taller at 6-foot-10 (2.08m). "But Rafa cames to me and we made a big hug, and it was kind of him".More news: Trump dodges London protests for tea with Queen Elizabeth
Both men are in the semi-finals at Wimbledon for the first time.
A sprightly Nadal went on the front foot to turn the tide in the fourth, Del Potro twice hitting the deck as he was broken to love to trail 3-2 and while he saved two set points behind his powerful serve, the 11-time French Open champion was jumping for joy after a searing backhand victor made sure the match would go all the way. "I'm not going to change that now", said the American.
"Beating Roger Federer at Wimbledon is definitely one I'm going to remember". I know in the semi-finals of Wimbledon you will not have an easy opponent in front (of you).
Nadal wasted a fourth chance at 7-6, before letting 2009 U.S. Open champion del Potro grab three points in a row for that set.
"But also putting myself in these positions where hopefully I'm able to get another step forward and be playing on Sunday".More news: Man dies as listeria outbreak recalls frozen food