"After nearly three years of serving in the Administration, I am going to be leaving to return to private life," Ross, a veteran US peace negotiator, said in a statement.
White House spokesman Jay Carney said that Ross, a special assistant to the President, played a key role at an historic time in the Middle East and North Africa.
"Dennis Ross has an extraordinary record of public service and has been a critical member of the President's team for nearly three years," Carney said confirming his resignation from the White House.
"When Dennis originally joined the Administration, he made it clear that given commitments to his family, he would remain for only two years.
"In light of the developments in the broader Middle East, the President appreciates his extending that by nearly a year and looks forward to being able to draw on his council periodically going forward," he said.
Ross said he is leaving the White House with mixed feelings.
"It has been an honour to work in the Obama Administration and to serve this President, particularly during a period of unprecedented change in the broader Middle East," he said.
"Obviously, there is still work to do but I promised my wife I would return to government for only two years and we both agreed it is time to act on my promise," Ross said.
"I am grateful to President Obama for having given me the opportunity once again to work on a wide array of Middle Eastern issues and challenges and to support his efforts to promote peace in the region," he said.
"A Middle East envoy to three presidents, Mr Ross, 62, is known for his painstaking approach to diplomacy and longstanding ties to Israeli leaders, which made him an important interlocutor with Israel behind the scenes, but also stood in stark contrast to the bolder instincts and more distant approach of his boss," The New York Times said.
Ross, who is the author of several books on diplomacy and statecraft, oversaw the drafting of a secret report for the president last year, which concluded that the Arab world was ripe for political upheaval and suggested ways for the United States to promote democratic reform, the daily said.