Open on Wednesday.
Tenth-seeded Nishikori registered his second consecutive big upset by edging third-seed Australian Open winner Stan Wawrinka of Switzerland 3-6 7-5 7-6 (7) 6-7 (5) 6-4 to become the first Japanese man in 81 years to reach a grand slam semi-final.
Russian left-hander Makarova made her best mark in grand slam singles by outslugging Victoria Azarenka, the U.S. Open runner-up the last two years, 6-4 6-2 in the women's quarters.
The 24-year-old Nishikori, who two days ago dismissed fifth seed Milos Raonic of Canada in a marathon five-set upset, put his name alongside compatriot Jiro Satoh who reached the last four at Wimbledon in 1933.
It was a further 15 years back when the U.S. championships had Japanese Ichiya Kumagae make it to the semi-finals.
"I don't know how I finished the game, but I'm happy," an exhausted Nishikori, who had a medical timeout in the third set to have his right foot taped, told the Arthur Ashe Stadium crowd after clinching victory in four hours and 15 minutes.
"I feel amazing. I'm very happy to come my first time semis. I hope I can recover again and hopefully I can play 100 percent tennis next round."
Nishikori will meet the winner of Wednesday night's quarter-final between top-seeded Wimbledon champion Novak Djokovic of Serbia and eighth-seeded Scotsman Andy Murray, the 2012 U.S. Open winner.
The Japanese scored the decisive break in the last game of the match, reaching match point after the eighth double fault of the quarter-final by Wawrinka, who also blasted in 18 aces.
In the women's quarter, 17th-seeded Makarova proved steadier and more explosive with her groundstrokes in dismissing the 16th seed from Belarus and advancing to the last four of a major for the first time after four losses at the quarter-finals stage.
Boldly going for winners at every opportunity against the former world number one, Makarova pressured Azarenka to a dozen break points and cashed in twice in each set for her victory.
"Finally I'm in a semi-finals, finally I'm here," gushed the 26-year-old Makarova, who is better known for her doubles exploits, told the Arthur Ashe Stadium crowd.
"It's a great feeling."
Makarova has hoisted major trophies but always as part of a partnership, as winner of the French Open doubles in 2013 with Elena Vesnina and in mixed doubles at the 2012 U.S. Open with Brazilian Bruno Soares.
The Russian, however, has thrived on her own racket in Flushing Meadows in the year's last grand slam by advancing without the loss of a set, eliminating seventh seed Eugenie Bouchard in overbearing heat in the process.
Makarova, who won her second career singles title at this year's Pattay City event in Thailand, will meet either two-time defending champion and top seed Serena Williams or 11th seed Flavia Pennetta of Italy for a berth in the final.
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- Victoria Azarenka