U.S. officials said the air strikes, carried out by drones, were the most significant attacks against the group in Afghanistan.
The U.S. military is still assessing the results of the strikes against the two leaders who were targeted at command-and-control locations in remote areas of Kunar province, Pentagon spokesman Peter Cook said in a statement.
U.S. officials, speaking on the condition of anonymity, said the air strikes, carried out by drones, were the most significant attacks against the group in Afghanistan in several years.
One of the targets was Faruq al-Qatani, who served as al Qaeda's leader for northeastern Afghanistan and had been assigned by the group's leadership to re-establish safe havens in the country, Cook said.
"He was a senior planner for attacks against the United States, and has a long history of directing deadly attacks against U.S. forces and our coalition allies," Cook said.
Al-Qatani, also known as Al-Nayf Salam Muhammad Ujaym al-Hababi, was named a "Specially Designated Global Terrorist" by the U.S. Treasury Department earlier this year for his role in al Qaeda.
The other, Bilal al-Utabi, was involved in "efforts to re-establish a safe haven in Afghanistan from which to threaten the West, and in efforts to recruit and train foreign fighters," Cook added.
A U.S. official, speaking on the condition of anonymity, said the strikes were carried out simultaneously against two different compounds.
Multiple Hellfire missiles were fired at each compound, the official said.
The United States had been looking for al-Qatani for four years and tracking and targeting him involved multiple U.S. agencies, the official added.
The official described al-Qatani as the No.1 al Qaeda official in Afghanistan, while al-Utabi was No.2 or No.3 in the hierarchy.
"If these strikes are determined to be successful, eliminating these core leaders of al Qaeda will disrupt efforts to plot against the United States and our allies and partners around the world, reduce the threat to our Afghan partners, and assist their efforts to deny al Qaeda safe haven in Afghanistan," Cook said in his statement.
American warplanes have conducted around 700 air strikes so far this year, compared with about 500 total last year, according to U.S. military officials, signaling a deeper role for American forces that is expected to continue for the foreseeable future.
With no end in sight for one of America's longest wars, any decisions on the future of the air strikes and nearly 9,000 U.S. troops that will remain in Afghanistan will be up to the winner of the Nov. 8 American presidential election.