Al-Zawahiri, an eye surgeon who helped found the Egyptian militant group Islamic Jihad, was named as the new leader of al-Qaeda on 16 June 2011, a few weeks after Osama Bin Laden's death has also praised recent Palestinian attacks against Israelis.
US-based SITE, which monitors violent extremist websites translated the message on Monday.
"The first matter is striking the West and specifically America in its own home, and attacking their interests that are spread everywhere," Zawahiri said, according to SITE.
"The supporters of Israel must pay with their blood and their economy."
He cited the 2013 Boston Marathon bombers Tamerlan and Dzokhar Tsarnaev as examples of lone wolf attacks.
He also hailed the past month's attacks by Palestinians against Israelis in Jerusalem and elsewhere in Israel and the West Bank.
A US-led coalition of countries has been bombing ISIS positions since August 2014.