Yet it was Nishikori who claimed two breaks to one in a tense decider, which saw him pegged back from 4-1 up before getting the job done.
Each of the Japanese's three Grand Slam semifinal appearances have come in NY and he exorcised some of the demons still lingering from his 2014 final heartbreak in Arthur Ashe Stadium by disposing of his attacker from that early September evening four years ago.
The No. 20 seed continued what's been a largely dominant run through the draw by winning in just 57 minutes, the third time in her five matches she didn't even have to play an hour. This is the first time in the Open Era when both the men and women semi-finals are represented by a Japanese.
"I've gotten a lot better managing my emotions once it gets to this part and knowing that everything is going to be probably more amped up", Keys said. "I feel it's a big chance for her".
Both players spoke to the umpire about the boisterous hum coming from the late-arriving Arthur Ashe crowd.
The 20th-seeded Osaka, a rising talent who won her first career title in March at Indian Wells, used a lethal ground game and solid serving to overwhelm a worn out Tsurenko, who laboured in stifling conditions on the Arthur Ashe Stadium court.
At the start of the match, Cilic has beaten Nishikori.
The two combatants received a standing ovation after one spectacular rally in the opening game of the second set, with even Sir Rupert rising from his seat.
Djokovic had won all 183 of his grand slam matches in which he'd enjoyed a two-sets-to-love lead.
Nadal sets up semi-final clash with Del Potro
The quarterfinal between Nadal and Thiem had night-match classic written all over it, and the Spaniard and the Austrian delivered. Thiem produced a stunning first-set performance to take the opener without losing a game but fell victim to a Nadal fightback.
Although the scoreline looks straightforward, Djokovic had to fight through the match.
Kei Nishikori turned the tables on Marin Cilic to reach the US Open semi-finals for the third time after another dramatic encounter at Flushing Meadows. Now, she needs to do it one more time to advance to her first career final.
John McEnroe was accused by American pro tennis player Mitchell Krueger of "ripping" Millman in the preview as the story continued that Federer lost the match because of the stifling NY heat and humidity rather than his opponent.
"You could imagine it was very hard for me to say goodbye before the match finishes", Nadal said.
This night was cooler, as the temperature dipped, but the humidity was above 80 percent, so with Millman drenched, he sought permission for a wardrobe change at 2-2 in the second set.
"I forgot about it [beating Djokovic]", said Nishikori. "I managed to win some big matches against them in the last couple of years, but also lost some". Tactically, you've got to find the right balance between being patient but constructive in the point, but at the same time be aggressive and take the chance when you have a shorter ball.
'He's got one of the best two-handed backhands in the game and very quick, ' Djokovic added. He was able to come through on only four of his 20 break points.
But Nishikori broke Cilic in the final game, capturing the match with a blistering service return.
Two inexplicable double-faults as the Japanese altered his return positions handed Nishikori the initiative and he produced a sumptuous backhand return victor down the line on set point to deepening Cilic's misery.