Isner, the No. 1 seed, won his second-round match, but Fish withdrew from the tournament with a right ankle injury just a few hours earlier.
"It's terrible luck for the tournament, I guess you could say, but it's even worse luck for Mardy," Isner said. "He's a guy who's been down on his luck this year."
Isner beat Ruben Bemelmans of Belgium 4-6, 6-3, 6-4 in the second round of the Atlanta Open on Thursday night.
Fish, the No. 2 seed and two-time defending champion, was leading Gilles Muller of Luxembourg 6-4, 3-2 when he pulled out.
"I think we're all wishing a speedy recovery for him," Isner said. "That's tough to swallow. He was winning that match and most likely was going to win it. That's terrible."
Isner will play 19-year-old Jack Sock, a 7-6 (5), 7-6 (5) winner over Steve Johnson in a matchup of wild cards.
The ATP World Tour said Nishikori and Soeda are the first two players from Japan to face each other in an ATP quarterfinal since the Open era began in 1968. Both players will represent Japan in the Olympics.
Isner's match was delayed 25 minutes after the second set when a circuit breaker overheated and turned off a bank of lights. After the power was restored and the third set started, the 6-foot-9 Isner hit seven of his 16 aces.
"I was sort of rushing prior to the lights going out because I had to change my clothes completely," Isner said. "I was gross. What takes the longest is redoing my socks and ankle bracelets. That takes forever, and I felt bad. When the lights came off, it gave me a lot of time. But I'd rather deal with that than deal with rain."
Thursday was the first day this week that rain didn't delay the tournament.
Fish was playing in 90-degree sunshine during the afternoon when he stumbled to his left while trying to return a drop in the second set. His left ankle appeared to buckle as he got near the steel net post.
"I did everything I could just to bring my head back," he said. "That brought my right leg out, sort of sliding and jarring it back and (turned) the inside of the right ankle. It was going to be either my knee, my ankle or my head. Thankfully it was my ankle."
After dropping his racquet and falling to the hard court, Fish stayed on his back for about a minute before limping to the sideline for a short break.
Fish returned to finish the fifth game of the second set with two aces. After he and Muller changed sides, Fish waved his opponent off.
On May 23, Fish had a heart procedure to correct an arrhythmia. He played in just one event, a fourth-round loss at Wimbledon to France's Jo-Wilfried Tsonga, from early April in Houston until Thursday.
Fish received a first-round bye in Atlanta and was playing his first match on the new courts at Atlantic Station.
"This is a comfortable place for me, so naturally I enjoy playing here," he said. "It's a bummer. What can you do? I've been in this position before. It happens."
Ebden, who teamed with Alex Bogomolov Jr. last year in Atlanta to win the doubles title, advanced to a quarterfinal for the first time since last October in Shanghai.
Bogomolov was upset as the No. 7 seed earlier this week by Sock, who has won three of four matches since returning from abdominal surgery four months ago.
Sock paired with Melanie Oudin to win the U.S. Open mixed doubles title last September. He won the junior boys singles title at the 2010 Open.
Johnson, who won the last two NCAA singles titles and led Southern California to four straight national team titles, dropped to 2-2 in his ATP career. He turned pro after winning his last 72 singles matches in college.