Both received walkovers when their semifinal opponents withdrew for health reasons. That left Nadal and Djokovic to play for the title Sunday in their 40th career meeting and their first of 2014.
It was the first time since at least 1968 that an ATP Tour event had two walkovers in the semifinals.
Djokovic was given a walkover for the second time in the tournament when Kei Nishikori withdrew because of a left groin injury. Four hours later, Tomas Berdych pulled out before his match against Nadal due to gastroenteritis.
''It's very unlucky, very unusual,'' Nadal said. ''Sorry for Kei, sorry for Tomas, and sorry for the tournament, especially sorry for the fans.''
Perhaps a thousand fans arrived at the stadium unaware the Nadal match had been canceled, and they jeered the announcement.
The wave of ailments left the tournament with only two women's doubles matches. Former No. 1 Martina Hingis advanced to her first doubles final since 2007 when she and Sabine Lisicki beat Cara Black and Sania Mirza 6-3, 6-4.
On Saturday, No. 1 Serena Williams will try for her seventh Key Biscayne title when she plays No. 2 Li Na - health permitting.
Tournament director Adam Barrett said the withdrawals by Nishikori and Berdych made it a tough day for the event.
''I ran into Cliff Buchholz, who was the tournament director before me for many, many years,'' Barrett said. ''He looked at me and said, 'Adam, that's never happened before. I think you just set a record.' I said, 'Cliff, not a record I want to set.'''
Djokovic also received a walkover in the third round and has played only six sets in the tournament. He's seeking his fourth title in the event, while Nadal is 0-3 in Key Biscayne finals, one of only three ATP Masters 1000 tournaments he has yet to win.
''To be able to play four finals in one tournament is because you did well,'' Nadal said. ''I'm going to try to be ready for Sunday.''
Djokovic will attempt to complete a March sweep Sunday. He won the Indian Wells title two weeks ago, when he beat Federer in the final.
Nadal leads his rivalry with Djokovic, 22-17, and they went 3-3 last year.
''Only chance to win against Novak is play to the limit, play my best, and wait that he not going to have his best day,'' Nadal said.
Regardless of Sunday's outcome, Nadal will remain No. 1 and Djokovic No. 2 next week.
Nishikori and Berdych both said they did what they could to feel better. Each pulled out less than two hours before his match.
''I tried to warm up and I couldn't move'' Nishikori said. ''With anybody on the other side, I don't think I could win today.''
Berdych has been beaten in his past 16 matches against Nadal, but the Czech blamed a virus - not the losing streak - for the stomach pains that hit him Friday morning. He said he became dehydrated despite receiving intravenous fluids.
''That's the worst basically that a tennis player can get,'' Berdych said. ''Without any energy or anything, you cannot do anything.''
Nishikori said his groin has bothered him for more than a month, and he retired during a match in Delray Beach last month. This week he won a won a three-set match against David Ferrer, saving four match points, and then beat Roger Federer in a three-setter Wednesday night.
Nishikori said he won't need surgery, but he's unsure how long he'll be sidelined and will fly home to Japan to see a doctor. His next scheduled match is in Davis Cup for Japan against the Czech Republic in Toyko on April 4.
Nishikori has retired or withdrawn 14 times in his career, including three times in Grand Slam events. He was hoping to reach his first ATP Masters 1000 final.
''It was going to be a great challenge for me today,'' Nishikori said. ''Hopefully I can play another time.''
Three of the past six Key Biscayne men's semifinals have been canceled. Nadal withdrew because of a knee injury in 2012, giving Andy Murray a walkover.
Spectators on Friday will be offered a chance to exchange their tickets for a session at the 2015 tournament.
''We will try to take care of all of our fans the best that we can,'' Barrett said. '' It's not an optimal situation.''