May, 43, a former Test and One-day International bowler, has been a high-profile fixture on the Australian cricket scene during his tenure, representing players' interests in everything from the Shane Warne drugs scandal to negotiations for better pay.
May said he was standing down because his family was relocating to the United States. He will stay on as chief executive of the International Players' Association.
The ACA said player payments had increased from 9.5 million dollars ($7.5 million) to 28 million dollars during May's time at the helm.
"His impact has changed the game forever, for the better," ACA president Ian Healy said.
Australian captain Ricky Ponting also paid tribute, saying modern players owed May a huge debt for looking after their interests.
"Whoever replaces him will have big shoes to fill," Ponting said.
A replacement is expected to be named in May.