The killings in Shkin, 130 miles south of Kabul, happened after unidentified assailants attacked a checkpoint of Afghan soldiers allied with American forces near the town, the military said in a written statement.
Two Harrier attack aircraft were called in and spotted two groups of five to 10 enemy fighters each. The jets attacked one of the groups with their cannons.
One of the planes then dropped a 1,000-pound laser-guided bomb. "Unfortunately, that weapon missed its intended target," Central Command spokesman Lt. Ryan FitzGerald told CBS News Radio.
"We do not target civilians intentionally," he said. "It's a tragic accident when things like this happen."
Four Afghan fighters were injured in the initial fighting and evacuated to a nearby U.S. base, the U.S. military said. They were in stable condition.
No U.S. soldiers were injured. It was not clear what happened to the enemy fighters.
The last major civilian casualties caused by American-led forces in Afghanistan occurred on July 1, when an Air Force AC-130 gunship attacked several villages in Afghanistan's Uruzgan province. Forty-eight civilians were killed and 117 were wounded, Afghan officials said.
Survivors said most of the dead were women and children who were attending a wedding in the town of Deh Rawood. They said the only gunfire from the area came from celebrants shooting their rifles into the air.
More than 10,000 foreign troops — 8,000 of them American — have been hunting down rebel fighters from the former Taliban regime, the al Qaeda network and their allies, including former Prime Minister Gulbuddin Hekmatyar.
There have been several rocket attacks and ambushes in recent weeks near Shkin, a key border crossing point from Pakistan. U.S. military officials believe rebel groups are launching incursions into Afghanistan from Pakistan.
Afghan authorities say Taliban remnants are reorganizing in an effort to destabilize the fledgling government of U.S.-backed President Hamid Karzai.
Southern Afghanistan in particular has been wracked by attacks in the last few weeks by suspected Taliban fighters. An International Red Cross worker was killed, and a U.S. military convoy ambushed. Two U.S. servicemen died in that attack.
Also Wednesday, Afghan authorities dispatched a team of mediators to northwestern Afghanistan to defuse tensions between two rival factions that clashed the day before.
Forces loyal to ethnic Uzbek warlord Gen. Abdul Rashid Dostum and those of his Tajik rival, Gen. Atta Mohammed, battled with automatic weapons for four hours Tuesday in Maimana, the capital of Faryab province, said Sayed Noor Ullah, one of Dostum's senior officials.
There were no immediate reports of casualties and it was not clear what sparked the fighting, Ullah said by telephone from the northern city of Mazar-e-Sharif. Maimana was quiet on Wednesday, he said.
Dostum and Mohammed agreed to work together after the Taliban government fell in 2001, but battles have broken out repeatedly between the two sides.
Ullah characterized Tuesday's skirmish as a "local dispute" between two commanders — Dostum's Mohammad Hashim and Mohammed's Gulam Farooq.