"It has been an honor to work in the Obama administration and to serve this president, particularly during a period of unprecedented change in the broader Middle East," said Ross, who is expected to leave before the end of the year.
"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."
White House spokesman Jay Carney said that Ross, a special assistant to the president, had played a key role at a "historic time in the Middle East and North Africa."
Ross played "a critical role in our efforts to apply unprecedented pressure" on the Iranian government and had also supported democratic transitions in the region, Carney said.
Obama would continue to periodically draw on Ross's counsel from outside the White House, Carney added.
Ross was known as a patient negotiator in the Middle East with deep ties to successive generations of Israeli leaders.
But his critics have sometimes whispered that he is too close to Israel in a way that hampers US efforts to serve as an honest broker in peace talks.
Ross, however, who also served president Bill Clinton, has spent long periods of time with Palestinian leaders, through years of frustrated US efforts to forge peace between Israel and the Palestinians.
He leaves at another uncertain moment in the history of testy ties between the Obama White House and the government of Israeli Prime Minister Benjamin Netanyahu and at a point where Israel-Palestinian peace talks have collapsed.
At a G20 summit last week, Obama was party to a conversation in which French President Nicolas Sarkozy called Netanyahu a "liar" and Obama also appeared to express annoyance with the Israeli leader.
"You may be sick of him, but me, I have to deal with him every day," Obama replied in comments that were translated into French and picked up on an open microphone.
Deputy US national security advisor Ben Rhodes on Wednesday insisted that Obama and Netanyahu had a close working relationship, and noted the Israeli leader praised the president warmly at the United Nations in September.
That praise followed Obama's efforts to block the Palestinian drive for statehood recognition at the UN, and his intervention with Egyptian authorities over a siege at the Israeli embassy in Cairo.
But relations between Obama and Netanyahu have generally been sensitive, as Israel has approved a series of settlement building schemes that have angered the Palestinians as peace talks were left stalled.
Obama came to power in 2009 determined to forge peace between Israelis and Palestinians and even called for a Palestinian state within a year at the United Nations in 2010.
But he has since seen his efforts founder and has become, like many of his predecessors, as Ross knows too well, frustrated with all parties in the intractable Israeli-Palestinian conflict.
Ross had also played a key role in building support for US efforts to punish and isolate Iran over its nuclear program.
But he will be leaving at a time of new tension, after the International Atomic Energy Agency (IAEA) issued a report saying Tehran had worked on the mechanics of a nuclear device.