Sherif Hazzaa, an Egyptian jihadist, said that al-Masri was dead and that he had spoken to him only a few days before in Syria. "He told me days ago: I do not carry my gun because I'm expecting to be targeted by a plane," Hazzaa said on Twitter.
Photographs circulating on social media purported to show the car that al-Masri was driving in when he was killed. They showed a grey car with its roof blown open by an apparent strike from above.
At least one bodyguard was also reported to have been killed in the strike.
If al-Masri is dead it would mark a bloody end to a long career in jihadism and a significant loss for al-Qaeda not just in Syria but in its global operations.
Al-Masri was one of the few prominent living al-Qaeda leaders of pre-9/11 era.
He was married to one of bin Laden's daughters and ran a guesthouse in Afghanistan where elements of the September 11 attacks were planned, according to the Soufan Group intelligence group.
"[His] significance in terms of his direct connection to the core of al-Qaeda and to some of its more infamous attacks is difficult to overstate," the group said.
After the US-led invasion of Afghanistan in 2001, Al-Masri and other leading al-Qaeda members fled into neighbouring Iran.
Iran has had a complicated relationship with Sunni jihadist groups like al-Qaeda, sometimes sheltering them against the US while also wary of their fundamentalist ideology.
Al-Masri and several others, along with their families, were essentially placed under house arrest by the Iranians and prevented from leaving Tehran.
He and four other al-Qaeda figures were freed in 2015 as part of a prisoner swap, according to the New York Times. The terror group released an Iranian diplomat kidnapped in Yemen in return.
Al-Masri appears to have headed to Syria soon after his release to take charge of al-Qaeda's increasingly ambitious affiliate there, known then as the al-Nusra Front.
With al-Masri's blessing al-Nusra split from the main al-Qaeda organisation and rebranded itself in an effort to appear as a more domestically Syrian group.
Western officials said the split was little more than a cosmetic move and that al-Nusra retained its al-Qaeda beliefs even as it operated under a different name.
Al-Masri is a nom de guerre that literally means "the Egyptian".
He is believed to have been born in Egypt under then name Abdullah Mohammed Rajab Abd al-Rahman and to have in the Egyptian Islamic Jihad group before joining al-Qaeda.