Nishikori began slowly against the Australian Open champion, but eventually got his bearings and used crisp returns and strong net play to edge ahead.
"Actually, I started a little bit tight, but my body was OK," Nishikori said in an on-court interview. "I don't know how I finished ... but I'm very happy."
In the semifinals, Nishikori will face No. 1 Novak Djokovic or No. 8 Andy Murray, who each owns a U.S. Open title and were to face each other in Wednesday's last match.
"Hopefully I can play 100 percent tennis next round," Nishikori said.
On Williams' second serve of her quarterfinal, she was called for a foot fault -- an unpleasant reminder of her meltdown after that very same ruling in the closing moments of a loss to Kim Clijsters in the 2009 U.S. Open semifinals.
This time, Williams was unfazed right afterward, and wound up winning the point when Pennetta's second-serve return found the net. But miscues by Williams led to an opening break, and after about 10 minutes of play, Pennetta -- a semifinalist in New York last year, but never a major finalist -- was ahead 3-0.
The sort of score that looks like a typo.
Didn't last long, though.
Williams began taking the ball inside the baseline as much as possible and finding the mark with her serves, putting more pressure on Pennetta while reeling off six straight games to take the first set.
Pennetta, who is into the doubles semifinals with partner Martina Hingis, might have been forgiven for giving up at that point. But she made things competitive again -- at least briefly.
Four aces in one game allowed her to lead 2-1 in the second set. That was pretty much that. Williams broke at love to go up 3-2, raising her left fist overhead to celebrate one particularly impressive shot, in which she raced back to the baseline to retrieve a lob, spun and smacked a forehand winner.
That was part of a 10-point run by Williams, who has not had a particularly difficult path so far through an upset-filled women's field.
She hasn't dropped a set, but she also has not had to face No. 3 Petra Kvitova, No. 7 Eugenie Bouchard, No. 8 Ana Ivanovic, No. 16 Azarenka or No. 24 Sam Stosur -- the last player to beat Williams at the U.S. Open, in the 2011 final.
All of those women were on Williams' half of the draw, and all lost to other players.
Azarenka, the runner-up to Williams at Flushing Meadows in 2012 and 2013, said she wasn't able to practice Tuesday because of food poisoning. But she did not want to talk about how that might have affected her play against Makarova, who won the last four games.
"You can ask me 20 times the same question. I'm not going to make any excuses today," Azarenka said, shaking her head. "As I said, I did the best I could today. I want to give full credit to my opponent. She deserves to win. She played much better than me today. That's it."
MAKAROVA BEATS AZARENKA: Ekaterina Makarova describes herself as a person who prefers "to stay in the shade."
At the U.S. Open, she finally believes she deserves to play under the brightest lights.
The 26-year-old Russian reached her first Grand Slam semifinal Wednesday, beating Victoria Azarenka 6-4, 6-2 at the U.S. Open. Makarova lost her previous four major quarterfinals.
"Before maybe I didn't believe that much that I can come through," she said. "Today definitely was a different feeling."
Azarenka acknowledged she suffered from food poisoning the day before but didn't want to talk about how it might have affected her. Unusually subdued for most of the match, she smashed her racket after one of her 27 unforced errors gave Makarova a break and a 4-2 lead in the second set.
"I'm not going to make any excuses," she said. "I did the best I could today. I want to give full credit to my opponent. She deserves to win. She played much better than me today."
The players were 16th and 17th in the seedings but came in with very different resumes. Azarenka is a two-time Australian Open champion who was defeated by Serena Williams in the last two U.S. Open finals.