"The Golan Heights will remain in the hands of Israel forever," Netanyahu said at the start of the cabinet meeting, in comments broadcast on public radio.
"Israel will never withdraw from the Golan Heights."
Israeli media have reported that Netanyahu planned the cabinet meeting as a statement amid fears Israel could come under pressure to return the Golan -- which it seized from Syria in 1967 -- as part of a future peace deal for its war-torn neighbour.
Urging the international community to recognise Israel's claim on the territory, Netanyahu said he told US Secretary of State John Kerry in a conversation on Saturday night that it was doubtful Syria can return to what it was.
The premier also plans to meet President Vladimir Putin in Russia, a key backer of Syria's President Bashar al-Assad, on Thursday.
"The time has come for the international community to recognise reality, especially two basic facts," Netanyahu said.
"One, whatever is beyond the border, the boundary itself will not change. Two, after 50 years, the time has come for the international community to finally recognise that the Golan Heights will remain under Israel's sovereignty permanently."
Israel fears Lebanese Shiite militia Hezbollah could establish a front against it along the Syrian border and that militants linked to Al-Qaeda and the Islamic State group could also pose a threat.
It is also concerned about the presence of its arch-enemy Iran in Syria, with Tehran supporting the Assad regime.
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Israel seized 1,200 square kilometres (460 square miles) of the Golan Heights from Syria in the Six-Day War of 1967 and later annexed it in a move never recognised by the international community.
Netanyahu's comments come amid a fragile ceasefire in Syria and indirect negotiations in Switzerland between Assad's regime and the opposition.
Brokered by Russia and the United States, the ceasefire deal does not include the fight against IS or Al-Qaeda's local Syrian affiliate.
The truce had largely held across parts of Syria since late February, despite frequent accusations that both sides were committing breaches.
But recent violence around Aleppo has sparked concerns that the ceasefire may not last, partly because rebels are involved in the battles there too.
Netanyahu said he told Kerry "we will not oppose a diplomatic settlement in Syria, on condition that it not come at the expense of the security of the state of Israel."
He said that meant "that at the end of the day, the forces of Iran, Hezbollah and (IS) will be removed from Syrian soil."
More than 270,000 people have died since Syria's conflict broke out in 2011, and millions more have been forced to flee their homes.
Israel has sought to avoid being dragged into the conflict, though Netanyahu publicly acknowledged for the first time last week that it had attacked dozens of convoys transporting weapons in Syria destined for Hezbollah.