In an audio recording posted online on Sunday, Zawahri called for the rebels to be patient, saying they should be prepared for a long battle with the Western-led coalition in Iraq and Syria and Iranian-backed Shi'ites fighting alongside Syrian President Bashar al Assad's government.
"Our people in Sham (Syria) prepare yourselves for a long battle with the Crusaders and their allies the Shi'ites and Alawites," the successor to Osama bin Laden said.
Zawahri said jihadists were targeted by their enemies because they sought to impose Islamic rule in Syria, adding that the West and its allies were doing everything they could to prevent an 'Islamic' wave that was sweeping the region.
It was not clear when the recording, in which the terrorist leader also said war in Syria was not just the prerogative of Syrians but all Muslims, was made.
He also warned terrorists not to turn the conflict into an purely internal Syrian one.
Syria's former al Qaeda branch Nusra Front now spearheads an alliance of Islamist brigades known as Hayat Tahrir al Sham which is leading battles against Syrian government forces and their Russian and Iranian backed allies on most of the main fronts in the country.
This alliance plays a key role in the control of most of Idlib province, although US led coalition strikes have killed dozens of its leaders in recent months.
(Reporting by Suleiman Al-Khalidi and Ahmed Tolba in Cairo)