Kuznetsova moved to No. 14 in the rankings after winning in San Diego last week, one above Sharapova, but Sharapova used a 31-11 advantage in winners to overcome 39 unforced errors in her Cincinnati debut. Kuznetsova committed only 17.
Sharapova said she lost a little focus after the first set.
"I didn't play the first game of the second set aggressively," she said. "It's the little things here and there. Tennis is a lot about momentum. I felt like I let her off the hook at the beginning of the second set. The only way to get that back is to be aggressive."
Kuznetsova needed treatment from a trainer on her back and left knee. She also squandered eight break-point opportunities in 10 tries but never thought about retiring.
"Even when I was down [in the third set], I felt like I still had chances," she said. "Even with my sore leg, I still felt like I had a chance to come back. I just didn't use my break chances."
Also on Tuesday night in the $2 million Western & Southern Financial Group Women's Open, top-seeded and defending champion Jelena Jankovic outlasted 71st-ranked Vera Dushevina 6-4, 3-6, 6-1 to advance to the third round.
Earlier, 15th-seeded Nadia Petrova became the third seeded player to be eliminated when temperatures in the mid 90s forced her to retire while trailing against Christina McHale.
McHale won the first set 7-6 (4) and was leading 5-3 in the second when the 21st-ranked Petrova retired because of heat illness. She became the second player to retire because of the heat, joining Olga Govortsova from Monday against 13th-seeded Shahar Peer.
McHale, ranked 132nd, was surprised to see Petrova retire.
"I'm not really sure what happened," said the American, whose biggest career win came at Charleston, S.C., in April when then-No. 9 Victoria Azarenka was forced to retire from their match. "I know she called the trainer, but I wasn't sure what she called the trainer for. I didn't try to focus too much on that. I'm just excited to move on to the next round."
McHale next plays qualifier Ayumi Morita.
Also Tuesday, No. 16 seed Marion Bartoli beat Alona Bondarenko 7-6 (4), 6-1 to reach the third round, 12th-seeded Yanina Wickmayer advanced to the second round with a 6-2, 6-2 win over Greta Arn and 11th-seeded Flavia Pennetta rolled to a 6-4, 6-1 win over Zheng Jie.
In other first-round matches, Sybille Bammer beat Sorana Cirstea 7-6 (5), 6-2, and Elena Vesnina eliminated Melanie Oudin 6-2, 6-3. Anastasia Pavlyuchenkova ousted Daniela Hantuchova 6-3, 6-1, and Maria Kirilenko cruised past Kateryna Bondarenko 6-1, 6-3. Andrea Petkovic knocked off Coco Vandeweghe 7-6 (1), 6-1, and No. 46 Gisela Dulko upset 26th-ranked Lucie Safarova 6-4, 6-3.
The 42nd-ranked Oudin, who reached the quarterfinals of the U.S. Open last year at the age of 17, managed just one winner against the 49th-ranked Vesnina.
"I saw on the screen after the first set that I have like 10 winners or eight winners or something and she has not even one, so for me, I was surprised, because I didn't remember that because I was so focused," the Russian said. "Yeah, maybe today she didn't play her best tennis, but I think I was playing today pretty well, and I was dominating through the whole match and trying to be aggressive.
"I was trying to play smart today, because she's a very smart player. She can read your game and be everywhere on the court, so for me today, the question was to try to be smarter than her," she said.
Oudin credited Vesnina's strong play.
"Today, it was pretty hard for me to hit a winner when she was being so aggressive so quickly," the Marietta, Ga., native said. "Normally, like when I play, I'm hitting a lot of winners, so that definitely was against me today. It kind of started going so fast and she wasn't missing and I was missing, because then I tried to go for too much. Just wasn't a good day."