The 10th seed braved on-court temperatures nudging the 40-degree mark to clinch a famous 6-4, 1-6, 7-6 (7/4), 6-3 victory over the world number one.
Nishikori, the first Japanese man since 1918 to reach the semifinals in New York, goes on to face Croatia’s Mrin Cilic who overwhelmed 17-time Grand Slam champion Roger Federer 6-3, 6-4, 6-4, in Monday’s championship match.
His victory over Wimbledon champion Djokovic will go down as one of the sport’s greatest shocks.
The 27-year-old Serb was the 2011 champion in New York, was playing in his eighth successive US Open semi-final and bidding for a sixth final, his 15th overall at the majors.
The top seed was also looking to make his third Grand Slam final of 2014.
In contrast, prior to Saturday, the 24-year-old Nishikori’s best effort had been a run to the quarterfinals of the 2012 Australian Open.
The Florida-based star also praised the work of coach Michael Chang, a Grand Slam winner with the French Open title in 1989.
Djokovic, playing in his 17th semifinal of the last 18 Grand Slam events, admitted Nishikori was the better player.