Shortly after the blast, militants fired at the troops with guns and rocket-propelled grenades. The military responded, calling in attack helicopters and fighter planes, according to a statement.
The attack occurred in Dihrawud district, Uruzgan province, as the service members were patrolling in an armored Humvee, along with Afghan forces, the military said.
An assessment of militant casualties is ongoing, the statement said.
"This is a sad and tragic day for us all," said Brig. Gen. John Sterling, a U.S. commander.
The names of the victims were withheld pending notification of next of kin.
The bombing raised the death toll of U.S. personnel in and around Afghanistan to 214 since the U.S. invaded the country in late 2001. The blast is the deadliest loss for U.S. forces here since five troops were killed in late September when their helicopter crashed.
Violence spiked across southern and eastern Afghanistan last year as militants stepped up their campaign against the country's U.S.-backed government. Some 1,600 people were killed, including 91 U.S. troops.
The past four months has seen an unprecedented spate of more than 20 suicide bombings, raising fears of Iraq-style bloodshed.
In other violence, a gun battle between militants and a U.S.-backed militia force in southern Helmand province Sunday left two militiamen dead and five missing, said Gen. Abdulrahman, the provincial police chief, who uses only one name. It wasn't clear whether the five fled the battle or had been kidnapped.
Five Afghan soldiers were wounded when a roadside bomb hit their vehicle in eastern Kunar province on Monday, Defense Ministry spokesman Gen. Mohammed Zahir Azimi said.
Another roadside bomb Monday hurt two Afghan soldiers in the capital Kabul, while a rocket attack on a security post in northern Baghlan city wounded two other troops, he said.
By Daniel Cooney