The American was killed when Afghan and US forces came under attack during a patrol on Monday in southern Zabul province's Day Chopan district, triggering a firefight, the US military said on Tuesday.
US and coalition aircraft provided air support during the clash, the military added.
According to initial estimates, at least 16 men, suspected fighters, were killed.
"We are greatly saddened by the loss of one of our own but are able to take solace in the fact that we are ridding this area of an oppressive and violent enemy," said US Brigadier-General James Champion.
"Afghan and US forces will continue this search and attack mission to ensure there are no enemy safe havens in this region," he said.
US forces to stay
The deceased US service member's name was withheld pending notification of the next of kin.
"Afghan and US forces will continue this search and attack mission to ensure there are no enemy safe havens in this region"
More than 17,000 US soldiers are still in Afghanistan after the US invaded in 2001.Violence since March, after a winter lull, has claimed more than 900 lives.
The American casualty follows the deaths of three US soldiers in eastern Afghanistan on Thursday.
Two drowned when their Humvee slid into a swollen river during a military operation east of the Jalalabad city; a third was killed by a roadside bomb that exploded near a US military vehicle in the eastern province of Paktika, near the Pakistan border.
More than 170 US soldiers have died in and around Afghanistan since the US-led invasion in late 2001.