The SANA state news agency said Abu Hammam al-Shami, also known as al-Farouq al-Suri, was killed in a special army operation in Idlib province on Thursday.
Al-Shami, a veteran al-Qaeda leader from Damascus, held the title of general military commander for al-Nusra Front.
Last week, members of the armed group had said he had been killed in a US drone strike.
But on Thursday, it said Shami had been killed earlier that day when he was in a meeting with other senior al-Nusra commanders.
Thursday's air strike came a day after the group claimed responsibility for a deadly attack on the intelligence headquarters of Syria's air force in Aleppo.
Al Jazeera's Zeina Khodr, reporting from neighboring Lebanon, said al-Shami was considered "the military brain behind" al-Nusra and that his death is a "huge blow" to the group.
Syria is fighting the Islamic State in Iraq and the Levant (ISIL) and al-Nusra Front.
Khodr said al-Nusra has pledged allegiance to al-Qaeda leader Ayman al-Zawahiri and has defeated moderate anti-Syria groups in the north.
"There were some forces in the al-Nusra Front contemplating the possibility to sever ties with al-Qaeda, and this is why analysts are saying that this strike could have been part of an internal power struggle," she said.
She added that the strike "was a major security breach, which means that there was some sort of intelligence information provided for the strike to have been carried out".
Colonel Steve Warren, a Pentagon spokesman, said, "We cannot confirm press reports of the deaths of senior al-Nusra leaders near the province of Idlib."
However, he added, "Neither the US or the coalition have conducted air strikes near that location in recent days."
Al-Nusra first surfaced on the internet in early 2012 to claim responsibility for suicide bombings in Aleppo and Damascus.
The well-armed group, with highly trained fighters, has since staged numerous attacks on security forces - as well as on other armed groups in the country.
Now, its leaders are reportedly considering cutting their links with al-Qaeda to form a purely Syrian entity.
According to the report, a rebranding could free up more funding, as al-Nusra is sanctioned by the UN Security Council and listed as a terrorist group by the US.