Isner, ranked 11th in the world entering the week and a U.S. Olympian, relied on his overpowering serve despite playing lethargically at times.
Isner is slated to face Nicolas Mahut in a second-round match. The pair met in the longest match in tennis history -- 11 hours, 5 minutes before Isner's 70-68 fifth-set victory in 2010 at Wimbledon.
"We can't avoid each other on grass," Isner joked about his pairing against Mahut. "I should have won my first-round match at Wimbledon (last month) and we would have faced each other."
But Isner knows he has to play better to advance. He felt like he was having trouble with Newport's grass surface most of the match.
"I didn't quite have my feet under me," he said. "I wasn't used to the court. That's something that comes with playing matches."
In the third game of the final set, Isner struggled to hold serve. When the game was over, the crowd became noticeably louder, trying to help him pick up momentum.
After Bubka double-faulted in the eighth game, Isner closed it with a backhand winner, going up 5-3 in the set. He closed out the match with a hard serve that Bubka was barely able to get his racket on, sending the ball sailing far wide.
In the first match of the day on center court, Nishikori was steady but unspectacular under nearly ideal weather conditions of mostly blue skies, temperatures in the low 80s with a slight breeze.
By climbing up the ATP rankings, Nishikori realizes he's been gaining a lot more attention at home because of his recent success. The 22-year old advanced to the third round at Wimbledon last month.
"Everything changed in Japan and other countries," he said. "I'm feeling a little bit of tension, but it's something you don't get normally. It's good. Everybody knows me on the street or whatever in the tournament, that kind of stuff."
Currently No. 18 on the ATP Tour, he was ranked as high as No. 16 earlier this year.
In other first-round play, third-seed Canadian Milos Raonic rallied past Matthew Ebden of Australia 3-6, 6-3, 7-5; American Sam Querrey, continuing his comeback from elbow surgery last year, ousted No. 5 seed and Russian Olympian Alex Bogomolov Jr. 7-5, 7-6 (5); American Tim Smyczek beat No. 4 seed Denis Istomin 6-3, 6-3; and 2009 Newport champion Rajeev Ram easily got past Grega Zemlja 6-3, 6-1.
Qualifier Benjamin Becker defeated David Goffin 6-4, 6-3; Izak Van Der Merwe outlasted eighth-seeded Gilles Muller 7-6 (5), 6-7 (3), 6-4; and Jesse Levine beat Marinko Matosevic 6-2, 7-6 (8). Former No. 1 in the world and Australian Olympian Lleyton Hewitt coasted by Canada's Vasek Pospisil 6-1, 6-1.
Querrey, a runner-up in 2009 at Newport, feels like his game is gaining momentum after the injury to his right elbow. He reached No. 17 in the world last year.
"In April this year, I felt like I was playing Top-20, Top-30 level even though I wasn't up there," he said. "I had like six or seven chunks of bone that were broken loose and I had to have those removed."