"Because the time has come for the world to move in a new direction," he said. "We must embrace a new era of engagement based on mutual interest and mutual respect and our work must begin now."
And in his first address to the 192-member General Assembly, watched intently by Iranian President Mahmoud Ahmadinejad, Obama warned that North Korea and Iran had put the world on a "dangerous slope" with their nuclear ambitions.
Libyan leader Moamer Kadhafi also took notes before stepping up to the podium directly after Obama, although the two men did not meet as Kadhafi delayed proceedings by gathering his notes at his seat.
Clad in sand-colored robes adorned with a black pin in the shape of Africa, a regal-looking Kadhafi spoke for over 90 minutes, breaking strict protocol in his first speech to the UN during his 40-year rule.
He railed against the supremacy of the five veto-wielding permanent members of the UN Security Council -- Britain, China, France, Russia and the United States.
"The veto is contrary to the UN Charter, the existence of permanent (council) members is contrary to the Charter," said the Libyan leader, the current chair of the African Union.
Kadhafi also accused the major powers of sparking many conflicts since 1945 in pursuit of selfish interests, and demanded that the West pay 7.77 trillion dollars in compensation for colonizing Africa.
As he spoke, some of his political opponents rallied outside the UN headquarters, but in a bizarre confrontation they were drowned out by a radical black American group lauding the "African King."
"Hey, hey, ho, ho, Kadhafi must go!" a 50-strong group of protestors, including Libyan exiles, chanted at the gates of the UN building.
Though known for his fiery and provocative rhetoric, Iran's Ahmadinejad was meanwhile due to send a message of peace to the assembly -- many of whom fear Iran's nuclear program has military aims despite Tehran's denials.
Obama called on leaders here to hold Iran -- as well as North Korea -- to account for their nuclear programs.
"If the governments of Iran and North Korea choose to ignore international standards, if they put the pursuit of nuclear weapons ahead of regional stability and the security and opportunity of their own people... then they must be held accountable," he said.
A day after a landmark climate summit, UN chief Ban Ki-moon opened the debate with a call for "genuine" collective action to roll back climate change and global poverty, and push for nuclear disarmament.
"If ever there were a time to act in a spirit of renewed multilateralism -- a moment to create a United Nations of genuine collective action -- it is now," Ban said.
All eyes were on Obama, who has vowed a close partnership with the United Nations after the administration of his predecessor, George W. Bush, was accused of riding roughshod over the world body.
But the US leader had some sharp words for the United Nations, saying "sadly, but not surprisingly, this body has often become a forum for sowing discord instead of forging common ground.
"After all, it is easy to walk up to this podium and to point fingers and stoke division. Nothing is easier than blaming others for our troubles, and absolving ourselves of responsibility for our choices and our actions."
And ahead of a UN Security Council meeting on nuclear disarmament he will chair Thursday, Obama warned "the threat of proliferation is growing in scope and complexity."
Israel has called for a symbolic protest against Ahmadinejad, suggesting representatives leave the chamber when the Iranian leader delivers his speech, but it was not yet clear whether many countries would comply or not.
China's President Hu Jintao and his Russian counterpart Dmitry Medvedev were also take to the floor on Wednesday.
---------------------------------------------------------------------------------------------------------------------------------