Syria’s representatives in the United Arab Emirates and Cyprus – who are husband and wife – are reported to have fled to Qatar.
It comes amid intensifying clashes in the key city of Aleppo, where troops are trying to halt a rebel advance.
UN members have traded more accusations of blame amid the diplomatic impasse.
Earlier, UN Secretary General Ban Ki-moon urged the world to “act now to stop the slaughter”, but Security Council members remain deadlocked over what action it should take.
The Syrian government has rushed troops and tanks to Aleppo, Syria’s second city and commercial centre, parts of which were seized by rebels.
The heightening of the crisis is causing regional concern, say correspondents, amid a growing exodus of refugees and fears the fighting could draw in Syria’s neighbours.
“We can confirm the defections of Syrian ambassadors to both the UAE and Cyprus,” White House spokesman Jay Carney told reporters aboard Air Force One.
Jay Carney said the move showed that “senior officials around the Assad inner circle are fleeing the government because of the heinous actions taken by Assad against his own people, and the recognition that Bashar al-Assad’s days are numbered”.
The diplomats in question are Lamia al-Hariri, Syria’s charge d’affaires in Cyprus, and her husband Abdelatif al-Dabbagh, ambassador to the UAE.
A military attaché at the Syrian embassy in Oman – Mohammed Tahseen al-Faqir – is also reported to have defected.
Earlier this month, Nawaf Fares, Syria’s ambassador to Iraq, left for Qatar.
A senior state department official told AFP news agency: “These defections serve as a reminder that the bottom is starting to fall out of the regime. It is crumbling and losing its grip on power.”
Aleppo is now the focus of a battle which neither regime nor opposition forces can afford to lose.
He says restive neighbourhoods are being pounded by artillery, mortars and helicopter gunfire, and there are multiple reports of reinforcements heading to the city.
One activist based in the city, Mohammed Saeed, told Associated Press news agency they were expecting a big assault to try to reassert government control.
Adrien Jaulmes, of French newspaper Le Figaro, said that many people had fled Aleppo and others remained off the streets and in their homes.
“All afternoon, helicopters and Syrian jet fighters have been circling above the city, with the Free Syrian Army fighters firing at them with all the weapons they have,” he said, adding that the situation remained fluid and difficult to assess.
The fighting has caused renewed regional concern, with Turkey tightening its border controls with Syria, though it says it will allow refugees to get through.
Thousands of refugees have already sought shelter in Turkey, Lebanon, Jordan and Iraq.
Meanwhile, AP reported Israelis were rushing to get government-issue gas masks on Wednesday, following a Syrian threat on Monday that it would employ chemical weapons against external attackers.
On Wednesday, the UN’s Ban Ki-moon urged world leaders to halt the slaughter in Syria.
But further bitter accusations of blame followed within the UN Security Council, which has seen three resolutions blocked by Russia and China.
“The Syrian people will pay the price for this failure [to act],” Germany’s UN ambassador Peter Wittig told a Security Council debate on the Middle East on Wednesday.
But Russia envoy Vitaly Churkin retorted that pledges by some Western powers to take steps to support the Syrian opposition outside the council “contributes and leads to an escalation of confrontation”.
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