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%, a huge change from the lacklustre participation in previous referenda, and 95% of the votes counted backed the motions.
Berlusconi, still reeling from crushing local election defeats last month, 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% 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 referenda," he said.
Berlusconi said the vote had probably ended any prospect of using atomic energy in Italy.
The referenda needed a turnout of more than 50% to be valid and met the target easily. Supporters of the proposals had been considered far more likely than opponents to vote.
The referenda could not have come at a worse time for the 74-year-old premier, who faces a sex scandal and three fraud trials and was weakened by crushing 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.
"Slap in the face"
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," said Roberto Calderoli, one of the League's senior ministers.
A stagnant economy, one of the world's highest levels of public debt and 30% youth unemployment are among the problems facing a government riven by divisions over issues ranging from tax to the NATO campaign in Libya.
Economy Minister Giulio Tremonti, widely credited with shielding Italy from the financial market crisis, has insisted on rigid budget discipline but faces growing opposition from cabinet colleagues alarmed that the policy is electoral poison.
A confidence vote in parliament on 22 June, intended to test the government's majority after a reshuffle last month, will be the next marker of whether Berlusconi has the support to see out his term until its scheduled end in 2013.
"Berlusconi has to show he is brave and launch an ambitious programme for the next two years. He should do it now, on 22 June in parliament," Interior Minister Roberto Maroni, another top Northern League leader, told the Corriere della Sera daily.
With speculation growing that cabinet divisions may bring down the government before the 2013 elections, the referendum provided a sharp snapshot of the electorate's mood.
Berlusconi has been a major supporter of atomic power, which the centre-right says is indispensable for the future of a country that imports nearly all its energy.
Aware of the likely backlash after the disaster at Japan's Fukushima reactor in March, the government had suspended its nuclear plans but a referendum could block them for decades.
One referendum repealed the "legitimate impediment" that allows ministers to skip trial hearings against them if they are on government business, which Berlusconi's critics say is for his personal benefit by possibly delaying his four concurrent trials.
Two others concerned the privatisation of water utilities. The government says privatisation is essential to finance better services, while opponents say it would lead to higher prices.
EurActiv with Reuters
