Israeli media estimated that some 15,000 protesters arrived at Netanyahu's state residence in Jerusalem where they carried banners calling on him to resign and to save Israeli democracy.
Saturday's protest was reported to be the biggest in a weeks-long weekly demonstrations near Netanyahu's residence in Jerusalem.
Protesters also arrived outside his private house in the Israeli city of Caesarea. Hundreds also gathered to protest in Tel Aviv.
Netanyahu faces nationwide protests over the state of the economy, hit by the coronavirus, further weakening his appeal to many in the Israeli public who find him unfit to lead the country while he faces trial for corruption charges, in which he denies wrong doing.
Netanyahu has rebuked the protesters, tweeting: "Don't drag the country towards anarchy, violence and attacks against the police."
But critics say Netanyahu - who normally receives high marks for his economic policies - appeared to lose interest in managing the crisis and failed to prepare a clear exit strategy after the first lockdown.