Officials said the missiles killed Ayman al-Zawahiri while he stood on a balcony at his home in downtown Kabul, Afghanistan, over the weekend in the biggest blow to the militants since Osama bin Laden was killed in 2011.
A senior administration official told reporters two Hellfire missiles were fired from an unmanned aerial vehicle at Zawahiri.
US officials said no one else was killed or wounded in the attack.
US officials said the CIA was responsible for the strike.
The agency declined to comment.
Hellfire missiles, mostly made by Lockheed Martin, are precision guided munitions for air-to-ground strikes that normally cause significant damage, taking down whole buildings and killing or severely injury anyone nearby.
Social media images of the strike pointed to the hallmarks of a modified Hellfire with six blades to damage targets and called the R9X, sources familiar with the weapon said.
It is largely aimed at individual targets, such as militants in Syria.
The images showed windows destroyed on the second floor while the structure of the house remained intact despite being hit by Hellfires.
More than 29 entities have Hellfire missiles but very little is acknowledged or publicly known about the modified version.
Officials believe the R9X is less likely to cause civilian casualties because instead of exploding, the missile cuts through targets with the sharp blades.
The MQ-9 Reaper, made by General Atomics, is the only drone that is publicly known to carry the Hellfire missile.
A Pentagon spokeswoman referred a query on the R9X missiles to US Special Operations Command, which would be the prime purchaser of the missile and had no immediate comment.
