Washington said the strikes on Sunday targeted Farouq al-Qahtani, Al-Qaeda's emir for northeastern Afghanistan, and his deputy Bilal al-Utabi, calling it the most significant attack against the group's leadership in several years.
Multiple Hellfire missiles "levelled" two different compounds in Kunar province where the men were believed to be hiding, US officials said Wednesday, without confirming if the strikes were successful.
Afghanistan's National Directorate of Security offered confirmation of their death on Thursday, adding that a third senior member of the group had also been killed.
"The attack was carried out in coordination with NDS," the spy agency said in a statement, without naming the third leader.
Pentagon press secretary Peter Cook had earlier said their demise would deal a blow to the militant group's presence in Afghanistan.
"Eliminating these core leaders of Al-Qaeda will disrupt efforts to plot against the United States and our allies, reduce the threat to our Afghan partners, and assist their efforts to deny Al-Qaeda safe haven in Afghanistan," Cook said.
The Pentagon had been actively hunting Qahtani for four years. He had longstanding ties with Osama Bin Laden before his death in the 2011 US raid on his Pakistan compound.
Qahtani had operated in Afghanistan since at least 2009 and was responsible for planning attacks against US and coalition forces in the country, officials said.
"He was seeking to re-establish (Al-Qaeda's) control in Afghanistan," a US official said.
"He was charged with the requirement to establish AQ safe-havens throughout Kunar and Nuristan provinces."
His deputy Utabi, was seen as the second- or third-most senior Al-Qaeda leader in Afghanistan, the official said.