Fazul Abdullah Mohammed had a $5 million bounty on his head for planning the bombings in Kenya and Tanzania that killed 224 people, including 12 Americans.
On Tuesday, Somali security forces shot and killed Mohammed at a security checkpoint in Mogadishu.
Somali officials said he was carrying sophisticated weapons, maps and tens of thousands of dollars.
They confirmed his identity later through pictures and a DNA sample.
Secretary of State Hillary Clinton called his death "a significant blow to /*al Qaeda*/."
"It is a just end for a terrorist who brought so much death and pain to so many innocents," she said.
Clinton honored the victims of the bombings during a visit to the American compound in Tanzania. She put flowers on a large rock just inside the main gate of the embassy, said a silent prayer and spoke with three Tanzanian employees who were at the embassy when it was bombed.
Mohammed's death is the third major blow against al Qaeda in the last six weeks. Navy SEALs killed /*Osama bin Laden*/ on May 2 at his home in Pakistan. Just a month later, Ilyas Kashmiri, an al Qaeda leader sought in the 2008 Mumbai siege and rumored to be a long shot choice to succeed bin Laden, was reportedly killed in a U.S. drone attack in Pakistan.
The Associated Press contributed to this report.