His declaration delivers a sharp blow to Maliki's efforts to hold on to power. The Shiite prime minister kept his job after 2010 national elections failed to produce a clear winner only with grudging support from Sadr, an old nemesis.
"If the head is reformed, everything beyond it is reformed," Sadr said about ways to fix the government.
Sadr has flirted with the prospect of abandoning Maliki for months. The two men have a bitter personal history, going back to when government forces targeted Sadr's militia at the peak of the 2006-08 sectarian fighting that almost pushed the country into civil war.
An adviser to Maliki, Ali al-Moussawi, declined to comment on Sadr's statements.
However, the prime minister's aides have previously predicted any vote to replace Maliki would fall short - as has Iraqi President Jalal Talabani, a Kurd.
Also Sunday, an Iraqi press freedom group condemned authorities for ordering the closure of 44 news organizations, including a U.S.-funded radio station. The country's media commission said it was only targeting unlicensed operations.
No media outlet is reported to have been forced to close so far. But critics say Maliki, whom they accuse of sidelining and silencing opponents in order to consolidate his Shiite party's power, is sending a warning to the media.
The dispute calls into question the future of Iraq's fledgling democracy, nine years after the ouster of Saddam Hussein and six months after the last of the U.S. troops who overthrew him withdrew.