"We are experiencing an unprecedented crisis in our international system," the president said, continuing the theme of an interview he gave to The Economist, published Thursday, in which he had warned NATO was experiencing "brain death" and the EU risked becoming insignificant.
The president, who has sought a prominent place on the international stage since coming to power in 2017, said "new ways of cooperation, new alliances" are needed between states and organisations.
The global political and economic systems constructed after the end of World War II, he added, had brought peace to some regions and helped lift many out of poverty.
But new inequalities have emerged between peoples and countries to cause the rebirth of nationalism and unilateralism "even among those who are the last-resort guardians of this international system," said Macron.
To face today's challenges - poverty, war, unchecked population growth, migration and dwindling natural resources - the world needed "more cooperation", not less, the president insisted.
And he warned there should be no "squeamishness or hypocrisy" when it comes to questioning the workings of multi-national bodies such as the United Nations, which he said had become "blocked".
Macron's interview with The Economist caused much controversy, with German Chancellor Angela Merkel saying his comments were "drastic" and US Secretary of State Mike Pompeo insisting NATO was "important, critical".
But the comments by Macron, who has made clear he wants a dialogue with Russian President Vladimir Putin, received warm backing from NATO non-member Russia.
Possibly taking aim at his critics, Macron said Tuesday that plain speaking was essential. "I think we need the truth... silence is not a solution," he said. German Foreign Minister Heiko Maas agreed there was a "need for action in international cooperation" including within NATO, adding it was good that such issues "are discussed openly".
At the same event Tuesday, EU Commission president-elect Ursula von der Leyen insisted that tackling today's challenges required "strong institutions and more effective multilateral cooperation".
"However, far too often the opposite is the case; existing powers are going down new paths alone, new powers are emerging, reemerging and consolidating."
She also said the EU needed to throw a heavier political punch on the international stage. Under her watch, Von der Leyen said, she hoped to make the commission "truly geopolitical".
"I want a more outward-looking European Union, a Europe which collectively defends our collective values and common interests in the world," she said.
Von der Leyen said multilateralism had created a post-war Europe finally "peaceful and united, settling our differences around tables rather than in between trenches".
"We should never forget how far we have come, and why," she said, joining Macron in warning against hegemony and nationalism, which the French leader said had been tested before and "gave us war".
China's Vice-President Wang Qishan also joined the call for greater global unity.
"The spread of unilateralism, protectionism and populism, and the tendency of replacing rational thinking and actions with the outpouring of emotions are not helpful in resolving problems," he told the peace forum.
"We are hopeful that countries can work together to reduce the peace deficit by expanding convergent interests, reinforce the safeguards for peace by upholding multilateralism and strengthen the bond of peace by encouraging dialogue among civilisations," he said.