The man, identified as Payenda Mohammed, was in command of more than 150 Taliban fighters in Uruzgan province. He was killed along with three of his men in a battle last week, a US military spokesman said on Monday.
"He was known for conducting rocket attacks, ambushes, guerrilla-style attacks and setting up illegal checkpoints," Colonel Jim Yonts told a briefing.
Taliban fighters are battling the government army and about 20,000 US troops across a rugged swathe of south and east Afghanistan.
Nearly 1000 people have been killed in violence this year, most of them fighters, but also 48 US soldiers.
The governor of Uruzgan province, Jan Mohammad Khan, said Payenda Mohammed was one of the main Taliban commanders in the province and was responsible for numerous attacks.
Fifteen Taliban fighters were wounded in the clash in Kandahar province on Wednesday, Yonts said.
US A-10 aircraft and attack helicopters were called in after the fighters took up positions in caves.
Vehicles and weapons were later found in the caves, Yonts added.