"I am stepping down as prime minister," he said in a television broadcast. "I hope the government's resignation will satisfy the people who came out in the streets."
He said it was right that responsibility for Friday's tragedy was taken by top officials and not just the three bosses of the Colectiv disco in Bucharest.
"I have to acknowledge the legitimate anger of the people," he said.
Demonstrators massed last evening in Bucharest's Victory Square, the seat of government, calling for Ponta's resignation and that of his interior minister, Gabriel Oprea.
The 43-year-old Ponta, prime minister since 2012, has been under growing pressure to quit after he went on trial in September facing charges of fraud, tax evasion and money laundering.
The charges date back to 2007-2011, when Social Democrat Ponta - the first Romanian head of government to stand trial while still in office - was working as a lawyer.
The toll from the nightclub fire would have been far worse but for the heroism of two men, physicist Claudiu Petre and drummer Adrian Rugina, who went several times into the burning club to rescue trapped revellers, only to die themselves.
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