Spokesman Maj. Mark McCann said the firefight occurred near Asadabad in Kunar province after two homemade bombs targeting coalition forces went off.
"Resulting from that engagement ... one U.S. soldier was killed and three were wounded," he told a news conference.
Kunar is part of a swath of southern and eastern Afghanistan where insurgents continue to defy the 18,000-strong U.S.-led force still hunting remnants of the former ruling Taliban regime and al Qaeda, three years after the Islamic hard-liners were ousted from power.
Col. Gary Cheek, the commander of U.S. forces in the eastern region, said he recently sent additional troops to Kunar to help persuade the local population to stop giving refuge to militants.
The mountainous area next to the Pakistani border is viewed as a stronghold of renegade Afghan warlord Gulbuddin Hekmatyar, a former prime minister who has joined the Taliban in vowing to drive out foreign troops and topple the U.S.-backed government.
"I am confident they (residents) will deny the sanctuary to the insurgents and we will drive them from the Kunar area," Cheek told the news conference.
Monday's clash came a day after one U.S. soldier and a former Afghan militia leader were killed in a gunfight when American troops tried to search the man's home in western Herat province.
McCann said the Afghan, Mullah Dost Mohammed, opened fire first.
He said Mohammed was targeted for involvement in "activities counterproductive to security."
At least 118 U.S. soldiers have died here since Enduring Freedom, Washington's anti-terrorism operation, began in late 2001.
This week's two American casualties are the first this year and also the first since the start of Operation Lightning Freedom, the latest phase of the U.S. military operation in Afghanistan, which began after Hamid Karzai's inauguration as the country's first directly elected president in early December.
The operation is supposed to bolster security ahead of parliamentary elections slated for April.
Also Sunday, unidentified gunmen robbed and tried to abduct an American aid worker in Kabul, but gave up when he resisted, the victim and Afghan police said.
About four men confronted the elderly American in a quiet back-street in the Afghan capital, snatching his bag and trying to force him into a waiting car, said local police official Sher Hussein.
The victim told an Associated Press reporter that the men "wanted to put me in the car." He said he was unhurt and that his bag contained only a few documents and some food, but declined to give his name or other details.
In other developments: