At least five attackers were killed in the battle, officials said.
In a brief statement, U.S. Central Command said the American soldiers were accompanied by troops of the Afghan National Army when they were attacked by "anti-coalition militia" in a village near Tarin Kowt.
The Americans were not identified by name or military unit.
Because of the location, the fighting did not appear to be directly related to reports that a senior member of the al Qaeda terrorist network, possibly, had been cornered by Pakistani forces near the Afghan border.
The battle in which the two Americans were killed happened in Oruzgan province on Thursday afternoon, the Central Command statement said. After being fired upon, the American soldiers fired back, killing at least five and wounding an undetermined number of others, the statement said.
The wounded Americans were evacuated to Kandahar airfield for treatment. The extent of their injuries was not disclosed. Their names were being withheld until relatives could be notified.