The 2015 deal reached between Tehran and the five permanent members of the UN Security Council plus Germany is a "solid, robust agreement that verifies that Iran will not build a nuclear weapon", Macron said.
"To reject it now without proposing anything else would be a big mistake and not respecting it would be irresponsible," he told the assembly.
Like Trump, he was addressing the world body for the first time but his message was very different, defending "multilateralism" rather than "survival of the fittest", while the US leader declared he would "always put America first".
In an interview with US TV channel CNN, Macron warned against scrapping the deal and called for the rhetoric against North Korea - which Trump threatened to "totally destroy" - should be toned down.
Climate deal not negotiable
The Cop21 climate agreement "will not be renegotiated", Macron declared, adding that the "door will be open" for the US to return.
"Unravelling this accord would be to destroy a pact between nations and generations," he said to applause.
Macron told the press that "sharing our disagreements" would bear fruit in the long run and won praise from Trump after meeting him.
Macron also called on the Un to become more efficient, saying the Security Council should not be "locked into a right of veto when mass atrocities are being committed", a clear reference to Russia's behaviour on the Syrian conflict.
But he also told the media that, while President Bashar al-Assad is a "criminal" who should "answer to international justice for his crimes", his departure should not be precondition for a peace deal "out of pragmatism".
That statement was welcomed by National Front leader Marine Le Pen on Wednesday, although she added that he made an "analytical mistake" in defending a multilateralism.