"Israel poses a danger on all people of this region...including Lebanon, and removing it is a Lebanese national interest," Nasrallah told hundreds of supporters in his half-hour speech.
"Some might think that the elimination of Israel is a Palestinian interest," Nasrallah said. "Yes, it is a Palestinian interest but not just that. It is in the interest of the entire Islamic world, it is in the interest of the entire Arab world and it is also in the national interest for every country in the region."
The charismatic Shi'ite cleric has lived mainly in the shadows, fearing assassination, since Hezbollah fought an inconclusive month-long war with Israel in 2006.
His last major speech came a month after that conflict, when he declared victory in front of thousands of supporters. Since then, he has made occasional and brief public appearances - most recently last September - but no lengthy public address.
Hezbollah emerged in the 1980s as the most prominent Lebanese faction fighting Israel's occupation of south Lebanon, but in recent months has lent its military support to President Bashar al-Assad's battle against Syrian rebels.
The militant group helped Assad's forces recapture a Syrian border town from the mainly Sunni Muslim rebels, an intervention which sharply escalated sectarian tension in Lebanon, where most Sunnis support the anti-Assad rebels.
Nasrallah said Hezbollah's enemies, including the United States, Israel and Britain, were trying to exploit the political tensions to drive a wedge between the Shi'ites and the rest of the region to marginalise their role in the Israeli-Palestinian conflict.
"We want to say to every enemy and every friend...we the Shi'ites of the world will not abandon Palestine, the Palestinian people or the sacred sites in Palestine," Nasrallah said, to loud cheers of support.
Security was heightened in the southern Beirut suburb where Nasrallah spoke, with gunmen stationed at intersections leading to the hall where he delivered his address. Buses were parked across the streets to prevent access to all but pedestrians.
The precautions were not academic. A huge car bomb hit the same Beirut district a month ago, two blocks from where Nasrallah was speaking, wounding 53 people.
Nasrallah gave his address on the occasion of Jerusalem Day, marked each year on the last Friday of the Muslim holy month of Ramadan in accordance with a tradition established by Ayatollah Ruhollah Khomeini, the late ruler of Iran and an implacable foe of Israel.