"Four US troops were killed in action but we have no indication that this was a new mine or an IED (improvised explosive device)," US military spokeswoman Cindy Moore said on Saturday.
She said the bodies of the soldiers had already been evacuated from the area, 40km southwest of Kabul, and an investigation was ongoing to determine the cause of the explosion.
The explosion took place in the Shur Endim area near Kandahar airport in the southern part of the country, Aljazeera's correspondent in Afghanistan reported.
Afghanistan is littered with old, unexploded mines after a quarter century of war, and it was not immediately clear if Saturday's deaths were the result of an unexploded or freshly laid device.
Saturday's explosion brings to seven the number of US soldiers killed so far this year in Afghanistan.
A US soldier was killed in the western region Herat in a mine blast earlier this month.