But it's far from a death blow, even in the wake of the assassination of Osama bin Laden by U.S. Navy SEALS in Pakistan May 2 and the loss since then of a half-dozen key al-Qaida commanders that has weakened the jihadist campaign.
With Awlaki's death Friday, the Americans may have succeeded in eliminating one of militant Islam's most articulate spokesman and charismatic recruiters who was able to relate to disenchanted Western Muslims.
But Awlaki, born, raised and educated in the United States, was probably not the operational chief of al-Qaida in the Arabian Peninsula that U.S. President Barack Obama and his security chiefs have trumpeted him to be.
"When considering the implications of Awlaki's death it is important not to overstate his role in AQAP," Texas global intelligence consultancy Stratfor observed.
"He was not the group's leader, as some in the media have claimed, and although he was a member of its Shariah Council, he was not even the group's primary religious leader."
Still, the demise of Awlaki and Khan, an American of Pakistani origin who was editor of AQAP's English language online magazine Insight, is expected to seriously impede the group's effort to radicalize Islamists in the West, the United States in particular.
AQAP is making great efforts to recruit people in the West, able to move around without attracting attention, to carry out terrorist attacks, individually or in small groups.
U.S. officials have been saying for some time that AQAP was seeking to form an alliance with al-Shabaab, the jihadist organization in Somalia across the Gulf of Aden from Yemen.
One reason could be the coterie of two or three dozen young Somalis who grew up in the United States as the children of immigrants that group has in its ranks, ideal for infiltrating the West.
It's not clear how close the groups are right now. But al-Shabaab appears to be divided between Arabs and other foreigners who espouse transnational jihad and the more nationalistic Somali faction whose primary objective is overthrowing Somalia's Western-backed transitional government.
With Awlaki and Khan gone, it may well be that AQAP's Saudi leader, Nasir al-Wahayshi, who has placed the group's full resources behind outreach to Western Islamists, will put more emphasis on wooing al-Shabaab's pool of potential recruits for attacking the United States and Europe.
New Mexico-born Awlaki had survived at least two U.S. airstrikes targeting him in the last nine months, underlining the importance the Obama placed on eliminating him.
Awlaki was held responsible for inspiring several attacks on the United States, including the Nov. 5, 2009, killing of 13 people at Fort Hood, Texas, allegedly by a Muslim U.S. Army psychiatrist, Maj. Nidal Malik Hasan, and the Dec. 25, 2010, attempt to blow up a U.S. airliner over Detroit.
Any plans by AQAP to avenge Awlaki's assassination may have to wait.
The group is fully occupied fighting Yemen's military, as well as the CIA detachment assiduously hunting it, amid the political turmoil of an uprising against President Ali Abdullah Saleh that appears to be on the cusp of becoming a full-blown civil war.
The CIA has boosted its presence in Yemen and the region, opening new drone bases in Ethiopia, the Seychelles and the Arabian Peninsula, in addition to the U.S. base in the former French colony of Djibouti in the Horn of Africa.
These days, Saleh, fighting for survival, is pulling out all the stops to help the Americans throttle AQAP because he wants them to back him.
He's been an unreliable ally to say the least and in recent weeks Washington has been pressing him to hand over power. He refuses.
But after he narrowly survived an assassination attempt in his Sanaa palace June 3, he seems to be going out of his way to secure U.S. support.
U.S. officials say it was intelligence from Yemen's security services that led to the attack that killed Awlaki.
So it's more than likely that there may be more covert operations to nail AQAP's leadership cadre in the weeks ahead.