Stating that the two US fatalities occurred in the vicinity of Deh Rawud, US military spokesman Major Mark McCann added that one soldier was wounded on Wednesday.
Residents of Deh Rawud said they saw three US soldiers being pulled from the wreckage of a vehicle that had been blown up by a mine or a roadside bomb, and being taken to helicopters for evacuation.
The blast occurred as the vehicle was crossing a dry river bed, they said.
The deaths came after Taliban guerrillas ambushed and killed an Afghan district official and two bodyguards in Deh Rawud on Tuesday night.
Hit and run
The official, Naseem Khan, who was in charge of finance in a district of neighbouring Helmand province, was killed in the village of Totai, Uruzgan police chief Rozi Khan said.
Taliban spokesman Abd al-Latif Hakimi said his men killed five and wounded two in the ambush.
Deh Rahwud is a stronghold of Taliban fighters who have been waging a hit-and-run campaign of attacks on US and Afghan government soldiers across south and southeast Afghanistan.
In southeast Paktika province, an Afghan was killed and another wounded on Tuesday night when four rockets fired at a US base missed and hit the nearby town of Orgune, the US military said in a statement.
Deh Rahwud in Uruzgan province
is a stronghold of Taliban fighters
There was also a rocket attack at the coalition's Bagram Air Base headquarters north of Kabul but there were no casualties, the statement said.
Separately, Taliban fighters on Wednesday torched a truck delivering water and other supplies to US-led forces in the southeast province of Khost but the driver escaped unhurt, a local official said.
An unmanned US aircraft also crashed in Paktia province, although it was the result of a mechanical failure rather than hostile fire, the US military said.
Southeast Afghanistan has seen a string of attacks on US-led forces in recent days.
More than 17,000 US-led troops are in Afghanistan fighting Taliban-linked fighters three years after a US-led military campaign toppled their government.