The move is not expected to significantly curtail drone attacks in Pakistan since Shamsi air base in southwestern Baluchistan province was only used to service drones that had mechanical or weather difficulties.
But Washington's decision to leave the base shows how the NATO attacks on November 26 have plunged the already strained US-Pakistan relationship to an all-time low. The crisis threatens US attempts to get Pakistan to cooperate on winding down the Afghan war.
Pakistan immediately retaliated by blocking its Afghan border crossings to NATO supplies and giving the US 15 days to vacate Shamsi - a deadline that expires on December 11. Islamabad is also boycotting an international conference in Bonn, Germany, aimed at stabilising Afghanistan.
US Ambassador Cameron Munter said in a local TV interview that Washington was doing its best to comply with Pakistan's demand to leave the air base.
"I think what we can promise you is that we will do everything we can to vacate the Shamsi base by the date that you asked us," said Munter.
Mohammed Naeem Mirwani, who owns land outside Shamsi, said two large military aircraft landed at the base Sunday morning and took off again in the afternoon after being loaded with containers.
US and Pakistani officials refused to comment on the aircraft.
Munter did not mention the use of Shamsi by American drones.
The US does not acknowledge the CIA-run drone program in Pakistan publicly, but American officials have said privately that the strikes have killed many senior Taliban and Al Qaeda commanders. US President Barack Obama has significantly stepped up strikes since taking office in 2009.
Pakistani officials regularly criticise drone attacks as violations of the country's sovereignty, but the government is widely believed to have supported the strikes in the past. That support has come under pressure this year as the US-Pakistan relationship has deteriorated.
Ties were damaged by a CIA contractor who shot and killed two Pakistanis in January, and the US raid that killed Osama bin Laden in a Pakistani garrison town in May. Pakistan was outraged because it didn't know about the operation against the Al Qaeda chief beforehand.
Pakistani officials pushed for US military personnel to abandon Shamsi following the bin Laden raid, but eventually agreed to a compromise with Washington. The US agreed to launch offensive drone strikes into Pakistan from American bases in neighboring Afghanistan, and restrict the use of Shamsi to drones that needed to land because of bad weather or mechanical difficulties, US and Pakistani officials said. They spoke on condition of anonymity because of the covert nature of the drone program.
That stance changed when NATO aircraft attacked two Pakistani army posts on the Afghan border before dawn on November 26, killing 24 soldiers and prompting the government to demand the US leave Shamsi air base.
The two sides have given differing accounts of what led to the attacks on the army posts.
US officials have said the incident occurred when a joint US and Afghan patrol requested air support after coming under fire. The US checked with the Pakistan military to see if there were friendly troops in the area and were told there were not, they said.
Pakistan has said the coordinates given by the Americans were wrong - an allegation denied by US defence officials.
Obama called Pakistani President Asif Ali Zardari on Sunday to offer his condolences for the deaths of the Pakistani soldiers and affirm the US is committed to a full investigation.