The strike came two days after a base in southern Syria, used by the US-led coalition fighting the Islamic State group, was assaulted.
"A US air strike today in northwest Syria killed senior Al-Qaeda leader Abdul Hamid al-Matar," said Central Command spokesman Army Major John Rigsbee in a statement.
There were no other known casualties from the strike, he said, adding it was conducted using an MQ-9 aircraft.
"The removal of this Al-Qaeda senior leader will disrupt the terrorist organization's ability to further plot and carry out global attacks," he said.
At the end of September, the Pentagon killed Salim Abu-Ahmad, another senior Al-Qaeda commander in Syria, in an air strike near Idlib.
"Al-Qaeda continues to present a threat to America and our allies. Al-Qaeda uses Syria as a safe haven to rebuild, coordinate with external affiliates, and plan external operations," Rigsbee said, according to AFP.
Last October, the US Army said it had carried out a drone strike against Al-Qaeda leaders in northwest Syria near the border.
The Syrian Observatory for Human Rights said 14 jihadists were killed in the strike, including five foreigners and six commanders.
Four years ago, a drone strike led by the US-coalition killed the deputy leader of Al-Qaeda, Abu al-Khayr al-Masri.
That year, an American air strike killed another Al-Qaeda leader in northern Syria, Mohammad Habib Boussadoun al-Tunisi.
