Suspected Taliban fighters clashed with Afghan and multinational forces in a four-hour gun battle on Saturday night in the Panjwayi district of Kandahar province.
The soldiers from the US-led multinational force died in hospital after the battle, one other soldier was wounded.
The fighting began when multinational forces engaged a group of between eight and 10 Taliban fighters.
"The enemy fighters attempted to flee the area, but then joined other reinforcements in a nearby compound," a spokesman for the US military said in a statement.
"Afghan and coalition forces pressed the attack with joint fires and a ground assault, killing an estimated 45 extremists in the firefight."
Another 25 Taliban fighters were reportedly killed in Panjwayi on Friday.
The Taliban controlled area is 35km southwest of the biggest city in southern Afghanistan, Kandahar - which is the scene of regular attacks blamed on the Taliban.
Panjwayi district is where Mullah Mohammad Omar, the fugitive leader of the Taliban, lived and is said to have first assembled the movement's religious scholars into a fighting force to rescue two girls abducted and raped by regional commanders.
Operation Mountain Thrust
Multinational forces have launched a massive anti-Taliban offensive – called Operation Mountain Thrust - in southern Afghanistan.
The operation is intended to "set the conditions" for a Nato-led force to take over command of the southern region in late July.
Mountain Thrust involves forces from Britain, Canada and the US, among other nations, as well as about 3,000 soldiers from Afghanistan's new army.
Hamid Karzai, the Afghan president, has called for more coordination between international forces and local leaders during counter-terrorist operations, a statement from his office said on Sunday.
Karzai urged international troops to work more closely with tribal leaders and community elders and repeated warnings that maximum caution should be taken to avoid civilian casualties during military operations.
He also urged the international community to identify the deeper causes and dynamics of terrorist activities.