Speaking on Monday, he denounced US policies as wicked because they turned the world against America.
"We need a new government, we need regime change in America," he said at the end of a visit to Cuba.
Farrakhan, who led the Million Man March on the Washington Mall in 1995 to promote black self-reliance, said the Bush administration's domestic policies were "sucking the blood of the poor and the weak".
The controversial African American leader defended Iran's right to develop a nuclear energy programme to reduce dependence on oil and said Washington's opposition was a pretext for a war.
"The Muslim world should unite against America's desire for a pre-emptive strike against Iran and Syria," he said.
Farrakhan said a similar pretext was used by Washington to invade Iraq "to rape the treasuries of the United States of hundreds of billions of dollars to be doled out to the friends of President Bush, Halliburton and Bechtel and associates".
Farrakhan visited Cuba for a week to learn about disaster management in the wake of the US government's failure to cope with Hurricane Katrina last year in New Orleans, he said.
He thanked Fidel Castro, the Cuban president, and blasted the US economic embargo against Cuba as a "wicked blockade".
The US government has no moral grounds to criticise Cuba, where education and health care are free, he added.