It booked his place in the Australian Open quarterfinals.
Dragged into a five-set dogfight for the third time in four rounds, Nishikori struggled to deal with the physical and mental strain early on as Carreno Busta took a two-set lead only for the eighth seed to claw his way back to level the contest.
Nishikori will next take on Serb Novak Djokovic after the world number one defeated Russia's Daniil Medvedev in the day's final clash.
The Japanese blew an early a break in the fifth set and was down 5-8 in the tiebreaker before reeling off five points to seal his victory in five hours and five minutes, much to the delight of his compatriots in the crowd at Margaret Court Arena.
"I feel like it's not enough," Nishikori joked courtside when reminded that he had spent 13 hours and 47 minutes on court in the first four rounds.
"It's not easy, of course. Today was the toughest match. I will try to recover well tomorrow."
The longest match of the tournament ended on a sour note as Carreno Busta cried foul over a line call while leading 8-5 in the final tiebreak.
After falling to defeat, he tossed his racquet bag across the court and screamed at the chair umpire.
"I'm very sad ... because after five hours fighting, after a five-hour match, the way that I leave the court wasn't correct and I'm so sorry," the world number 23 said in his post-match news conference.
