The airstrike represents the first American military assault on Afghanistan since troops withdrew from the country.
According to the Washington Post, al-Zawahiri was killed after he stepped onto the balcony of a safe house in Kabul, where he had been residing with members of his family. No other casualties have been reported.
Two missiles in total were fired. Al-Zawahiri reportedly had a $25 million bounty on his head. Senior US security officials had been working on the specific operation since early April.