This comes as peace talks in Nigeria stalled, with a deadline for a peace agreement in Darfur extended by 48 hours.
African Union mediators, under US pressure, extended the deadline after rebels rejected a peace proposal that would end the conflict that has killed tens of thousands of people.
The conflict has surged as major issue in Washington with protesters converging on the National Mall near the Capitol that houses the US Congress, seeking to "Save Darfur Now".
Mr Clooney -- who visited Darfur last week along with his father Nick, a former journalist -- addressed the crowd, calling on people to take action.
"This is in fact the first genocide of the 21st century. But there is hope, there is all of you," said Mr Clooney.
His father said: "We didn't stop the Holocaust. We didn't stop Cambodia. We didn't stop Rwanda. But this one, we can stop."
Holocaust survivor and Nobel laureate Elie Wiesel said: "Silence helps the killer, never the victims."
"For the sake of humanity, save Darfur," he told the mostly young crowd.
Demonstrators cheered calls for US and international action from a wide range of religious leaders, activists, politicians, celebrities and athletes.
Similar rallies were announced by around 1,260 groups in more than a dozen US cities, including Austin, Texas; Chicago; San Francisco; and Seattle in the US state of Washington, as well as Toronto and Vancouver, Canada.
Sanctions
The United Nations has slapped sanctions on four Sudanese leaders for their role in the Darfur carnage and has been discussing a beefed-up UN peacekeeping force.
Earlier, US Secretary of State Condoleezza Rice made clear growing US impatience with some governments for their reluctance to confront Sudan.
"We also do need more support, frankly, from other members of the international community, from China, from Russia, which abstained on this (sanctions) resolution," she said.
The US wants to expand a beleaguered 7,000-member African Union peacekeeping contingent in, Darfur into a large UN force with greater logistical support from NATO.
US President George W Bush, who has labelled the Darfur violence "genocide", endorsed the rallies, after meeting with activists lobbying on behalf of victims on Friday, and pressed the Sudanese government to end the violence in the region.
The Sudanese embassy in Washington issued a statement on Friday calling the protests "misdirected" and "naive."
48-hour extension
African Union negotiator Salim Ahmed Salim said the deadline for a provisional deal had been extended with only a few hours to spare, after rebels rejected a draft peace agreement.
Rebels were earlier urged by UN representative Sudan Jan Pronk to sign the deal, but two rebel groups announced their refusal to sign while the AU insisted the content of the agreement would not be changed, ahead of the deadline.
The peace plan the government agreed to requires it to disarm Janjaweed militias before the rebels lay down their weapons in what diplomats said was a major breakthrough.
But the rebels, under intense international pressure to also accept the 85-page settlement drafted by AU mediators, said they would not accept the deal.
The rebel Sudanese Liberation Movement (SLM) and the Justice and Equality Movement (JEM) had issued statements of a "joint position" not to sign the AU-brokered peace accord.
"This document is not acceptable to us, and we are not going to go by it or sign it," JEM spokesman Ahmed Hussain said.
Reservations raised by the rebels include claims that the AU document did not consider giving the vice presidential political post to the Darfur region, or adequately resolve other power-sharing and wealth-distribution issues.
The government said it had decided to sign despite "reservations", and diplomats said the biggest of those centred on disarmament arrangements.
Mr Pronk originally insisted the deadline would have to stand. “A couple of hours' slip is no problem, of course, you can stop the clock and continue," he said after the afternoon meeting.
He added that the AU document was "workable", but warned the rebel parties would have to bear the "political consequences" if the Sudanese government signed but they failed to do so.
Rebels took up arms in early 2003 in ethnically mixed Darfur, an arid region the size of France, over what they saw as neglect by the Arab-dominated central government.
Khartoum used militias, known locally as Janjaweed and drawn from Arab tribes, to crush the rebellion.
The fighting has killed tens of thousands of people while a campaign of arson, looting and rape has driven more than 2 million from their homes into refugee camps in Darfur and neighbouring Chad.
All sides have continued fighting despite a 2004 ceasefire, according to the AU, which has 7,000 peacekeepers in Darfur.