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In the past, Ayatollah Ali Khamenei has called Israel a "cancerous tumor" that must be wiped from the map, but the new comments mark the first time in years he has openly speculated about Israel's demise.
"Definitely, the day will come when nations of the region will witness the destruction of the Zionist regime," Khamenei was quoted as saying. "How soon or late (Israel's demise) will happen depends on how Islamic countries and Muslim nations approach the issue." He did not elaborate.
Khamenei's comments come as the world marks International Holocaust Remembrance Day on Wednesday, the 65th anniversary of the liberation of the Nazi-run Auschwitz death camp.
Iran does not recognize Israel, and the two countries have been bitter enemies since Iran's Islamic Revolution in 1979, and current Iranian President Mahmoud Ahmadinejad called for Israel's destruction.
Tehran is accused of supporting Lebanon's Shiite Muslim militant group, Hezbollah, which fought Israel until it withdrew it soldiers from southern Lebanon in 2000. Hezbollah continues to launch occasional attacks against Israeli troops in a disputed strip of land on Lebanon's southern border. Iran also backs Hamas, the Islamic militant group that controls the Gaza Strip.