Thousands of Palestinians came under fire as they gathered along border fences to demand the right to return to homes, now on Jewish land, which they abandoned during wars with Israel in 1948 and 1967.
Israeli soldiers killed at least two protesters and wounded 15 more after dozens cut their way through the fenced ceasefire line separating Syria from the occupied Golan Heights, seized by Israel during the Six Day War of 1967.
Ten refugees were shot dead on the Lebanese side of the border with Israel and one protester was killed in Gaza.
The mass protests represented an unprecedented civilian challenge to Israel from neighbouring territory and catapulted the Jewish state into the maelstrom of the Arab uprisings for the first time.
Inspired by popular revolts elsewhere in the Middle East, activists are believed to have orchestrated the march on Israel's borders in secret by using social networking sites like Facebook.
Israel had been expecting local unrest as Palestinians marked the 'Nakba', or 'catastrophe', that saw the creation of the world's largest refugee population when 700,000 people fled or were forced out of their homes during the establishment of the Jewish state in 1948.
But its military was caught entirely by surprise as thousands of Palestinian refugees marched through mined territory to reached the fenced ceasefire line dividing Syria from the Golan Heights.
Israeli military officials accused Bashar al-Assad, the Syrian president, of orchestrating the infiltration to distract public attention from his brutal suppression of domestic protests against his rule in which more than 700 people have died.
The ensuing bloodshed, reprised shortly afterwards on the Lebanese border, thrust Israel into an immediate confrontation with its neighbours and prompted fears of a fresh uprising, or intifada, within the Palestinian territories.
Although Israel has faced invasion from its Arab neighbours several times, it is the first time civilians have tried to penetrate its bristling defences in a concerted manner.
But as Arab condemnation poured in, Benjamin Netanyahu, the Israeli prime minister remained defiant, insisting that he would respond to cross-border challenges, whether mounted by soldiers or civilians, in a robust manner.
"Nobody should be mistaken," he said. "We are determined to defend our borders and sovereignty."
Israeli officials said the military had no choice but to respond after protesters who reached Majdal Shams, a Syrian Druze village in the northern Golan Heights, threw stones and Molotov cocktails.
But a Druze witnesses said the protesters were peaceful.
"The people came in a peaceful way, they had no weapons," said Taiseer Maray, who runs a medical charity that treated the wounded. "In a peaceful way they stated that they had waited for 60 years and wanted to go back to their homes. But the Israelis shot directly at the people, even though they posed no threat."
Thousands of refugees penetrated Lebanese army lines to reach the border fence but their progress was halted by Israeli gunfire.
(Pls keep) After sporadic violence in the West Bank and East Jerusalem throughout the day, news of fatalities elsewhere led to escalated tension and there were fears that the next few days could bring more unrest and perhaps even a sustained uprising.
Fanning those concerns, Hamas, the Islamist overlords of Gaza, said Israel's violent response to the protests represented "a turning point in the Israeli-Arab conflict".