Djokovic, who launched the breakaway organisation alongside Canadian player Vasek Pospisil in 2021, said he had "ongoing concerns regarding transparency, governance, and the way my voice and image have been represented".
The PTPA last March launched legal action against tennis' governing bodies, including the ATP, WTA, International Tennis Federation and International Tennis Integrity Agency, accusing the organisations of "systemic abuse, anti-competitive practices, and a blatant disregard for player welfare".
Djokovic, though, admitted at the time he disagreed with parts of the lawsuit, while the ATP and WTA both hit back strongly at the PTPA's allegations.
And the 24-time grand slam champion has now ended his involvement with the union as he goes into a new tennis year, set to resume his quest for a record-extending 25th grand slam singles title when he seeks an 11th Australian Open crown in Melbourne.
Djokovic said on X: "After careful consideration, I have decided to step away completely from the Professional Tennis Players Association.
"This decision comes after ongoing concerns regarding transparency, governance, and the way my voice and image have been represented.
"I am proud of the vision that Vasek and I shared when founding the PTPA, giving players a stronger, independent voice - but it has become clear that my values and approach are no longer aligned with the current direction of the organization.
"I will continue to focus on my tennis, my family, and contributing to the sport in ways that reflect my principles and integrity. I wish the players and those involved the best as they move forward, but for me, this chapter is now closed."
The PTPA said in a statement late on Sunday that players had created the body to secure a stronger and more transparent voice in professional tennis and it was open to addressing any issues.
"The PTPA is governed by players and operates with open communication, collaborative decisions and regular engagement. We always welcome the opportunity to address issues with any player, and remain available to do so," it added.
The PTPA said in November that it was close to a deal with Tennis Australia, which is gearing up for the Australian Open beginning on January 18, the start of a new grand slam year.
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