Voters back motions against nuclear power, water privatisation and trial immunity for government ministers.
The proposals to repeal Berlusconi-era legislation on nuclear power, water privatisation and trial immunity for government ministers were backed by opposition parties and opposed by the centre-right.
Interior ministry figures put the turnout at 57 per cent, a huge change from the lacklustre participation in previous referendums, and 95 per cent of the votes counted backed the motions.
Berlusconi had declared that he would not cast a vote, but the unusually high turnout dashed any hope he may have had that the necessary quorum of 50 per cent would not be reached.
He said in a statement that the government would accept the "clear" result of the vote.
"The government and parliament now have the duty to fully accept the result of the four referendums," he said.
The referendums needed a turnout of more than 50 per cent to be valid and met the target easily. Supporters of the proposals had been considered far more likely than opponents to vote.
The referendums could not have come at a worse time for Berlusconi, 74, who faces a sex scandal and three fraud trials and was weakened by heavy losses in last month's local elections, including in his northern power base, Milan.
The centre-left opposition campaigned hard to get voters to the polling stations. The last referendum to reach a quorum was in 1995. Six have been declared void since then.
Pierluigi Bersani, leader of the centre-left Democratic Party, said it had been "an extraordinary day" and repeated a call for Berlusconi to resign.
More ominously for the ruling centre-right, Berlusconi's coalition allies in the Northern League appeared to be losing patience after weeks of acrimony, raising the possibility of a split that could cost the government its majority.
"In the local elections two weeks ago we had a slap in the face, now with this referendum we've had the second slap in the face and I don't want this to become a habit," Roberto Calderoli, one of the League's senior ministers, said.
A stagnant economy, one of the world's highest levels of public debt and 30 per cent youth unemployment are among the problems facing a government riven by divisions over issues ranging from tax to the NATO campaign in Libya.
Al Jazeera and agencies