The 248th-ranked Kleybanova, who received a wild card entry into the tournament, dropped the first set to Johanna Larsson of Sweden before rebounding to secure a 2-6, 6-3, 6-2 victory at Key Biscayne on Tuesday.
Kleybanova was diagnosed with Hodgkin's Lymphoma last May and it has been 10 months since the 22-year-old Russian played a professional match.
"I'm really happy I won the match, but I really enjoyed playing," Kleybanova said. "It's not like if I didn't win it today I would be all mad.
"Just to feel again all those emotions was really great and something I missed the most from tennis."
Kleybanova said she was constantly getting sick last year with flu-like symptoms and fatigue that would go away for a while and come back.
Finally, after she lost to Shahar Peer of Israel in the second round of the 2011 Rome tournament in May, she decided to undergo complete medical testing.
The diagnosis came as a shock. But her competitive instincts went into overdrive as she prepared to battle cancer.
"Doing professional sport you always have something, some pain," Kleybanova said. "You have so much fatigue every day.
"No one was expecting something like that, but on the other hand I knew something was wrong and I wanted to figure out what was wrong. I knew it was going to be a very tough time for me, another big fight and take a long time, so I had to be focused."
She underwent chemotherapy treatment until December. She was treated in Rome where her boyfriend, Italian professional volleyball player Giacomo Rigoni, lives.
Kleybanova, who will play fellow Russian Maria Kirilenko in the second round, looked rusty in the first set. But she picked up her play to take care of the 64th-ranked Larsson.
"It's amazing but it's not just about the win," she said. "I was always trying to be positive and even though I lost the first set I tried to stay out there.
"For me, it's not like I won the tournament," Kleybanova added. "For the rest of us, in normal conditions, I just won the first round. For me, inside, it was really emotional, and for my coach and friends who were out there."
By the time Kleybanova went 4-1 up in the second set, Larrson was losing her cool. She threw her racket to the court at the end of that fifth game, and had further meltdown moments throughout the match.
Kleybanova failed to take advantage of three match points at 0-40 with Larsson serving at 1-5 in the third set.
She closed out the match on her own serve in the next game, but it took some serious effort. She went down 30-40, but fought back for the win, taking the match when Larsson netted a forehand.
"I'm happy I was there for three sets which is a good test for me, I think, for the first match," Kleybanova said. "I'm happy for the way it went because I didn't know what to expect."
Tuesday's schedule only featured 12 women's first-round matches.
Heather Watson of Great Britain, another wildcard recipient, won a tough 6-3, 3-, 7-6 (4) winner over Sorana Cirstea of Romania.
Ekaterina Makarova of Russia, the player who upset Serena Williams at this year's Australian Open, outlasted Jelena Dokic 6-1, 7-5.
Mona Barthel of Germany defeated Greta Arn of Hungary 6-1, 6-0.