The 29-year-old midfielder clinched the honour ahead of Iran's Hadi Aghily at Wednesday evening's ceremony in Kuala Lumpur.
Djeparov, who won the award in 2008, played a key role in helping Uzbekistan to their best ever Asian Cup finish, placing fourth at the 2011 tournament in Qatar.
"I'm very happy to have won this award for the second time after winning it three years ago in 2008," Djeparov said.
"I believe every player has this dream to win this award and I believe this is not the end for me as there will be more in the future.
"This second time round, I'm even happier than last time. I hope this award is good for my career now with Al Shabab.
"Football is the same everywhere, It depends on the player how to play from one country to another. Every player should play professionally every time regardless in which country he plays."
Nominees Keisuke Honda, Shinji Kagawa, Koo Ja-Cheol and Yeom Ki-Hun were unable to attend the evening and were subsequently ineligible.
Meanwhile, Aya Miyama won the Women's AFC Player of the Year award, after her role in Japan's 2011 Women's World Cup triumph.
Japan won both the men's and women's National Team of the Year honours, while Al Sadd claimed the club award.
Full list of awards:
Player of the Year - Men: Server Djeparov (Uzbekistan)
Player of the Year - Women: Aya Miyama (Japan)
Youth Player of the Year - Men: Hideki Ishige (Japan)
Youth Player of the Year - Women: Caitlin Foord (Australia)
Club of the Year - Al Sadd (Qatar)
National Team of the Year - Men: Japan
National Team of the Year - Women: Japan
Referee of the Year - Men: Ravshan Irmatov (Uzbekistan)
Referee of the Year - Women: Sachiko Yamagishi (Japan)
Assistant Referee of the Year - Men: Rasulov Abdukhamidullov (Uzbekistan)
Assistant Referee of the Year - Women: Sarah Ho (Australia)
Coach of the Year – Men: Norio Sasaki (Japan)
Coach of the Year – Women: Takako Tezuka (Japan)
Futsal Player of the Year: Mohammad Keshavarz (Iran)
Futsal Team of the Year: Nagoya Oceans (Japan)
Fair Play Award: Korea Republic
Member Association of the Year: Japan
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