Sharapova, making her Cincinnati debut, battled to a 6-4 1-6 6-2 victory.
"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," she said.
Kuznetsova, who won Sunday's San Diego Open final, needed treatment from a trainer on her back and left knee.
But she refused to blame her injury problems for the defeat.
"Even when I was down, I felt like I still had chances," stated Kuznetsova.
"Even with my sore leg, I still felt like I had a chance to come back. I just didn't use my break chances."
Sharapova broke her opponent in the ninth game of the opening set to take control of the match.
But Kuznetsova, the first Russian to win the US Open with her victory in 2004, roared back by sweeping through the second set in only 30 minutes.
Former world number one Sharapova seized the initiative in the decider, going 3-0 up before breaking Kuznetsova a second time to close out the match.
Top seed and defending champion Jelena Jankovic opened with a victory after a 6-4 3-6 6-1 second round win over Russia's Vera Dushevina.
The 11th seed Flavia Penetta defeated China's Zheng Jie 6-4 6-2, while 12th seed Yanina Wickmayer of Belgium beat Hungarian qualifier Greta Arn in straight sets 6-2 6-2.
Also through are Russia's Elena Vesnina, former Wimbledon finalist Marion Bartoli and American wildcard Christina McHale who advanced after 15th seed Nadia Petrova was forced to retire because of heat illness.
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