"Given the enormous price paid already by the Syrian people... it is more urgent than ever to act to overcome differences in favour of a political transition," Le Drian told a security forum in the United Arab Emirates.
He said the change should be "a transition in which president Assad would no longer keep his place".
Le Drian spoke of a "tragedy" and accused Assad and his family "of clinging to power by multiplying the daily massacres and atrocities".
The minister's remarks came after the umbrella opposition National Council on Friday refused to accept Assad in any talks on ending Syria's 23-month conflict, as part of a "framework" it has drawn up for a political solution.
China and Russia have blocked three resolutions at the UN Security Council that would have threatened sanctions against the Assad regime over its brutal crackdown on democracy protests that erupted in March 2011.
The crackdown triggered an armed uprising, and the United Nations says the conflict has killed nearly 70,000 people.
On Iran, the French minister stressed the need to prevent Tehran from developing nuclear weapons, and said sanctions imposed on the Islamic republic were aimed at pushing it into serious negotiations.
"The progress of Iran's programme only adds to our concerns" about the unacceptable "possibility of Iran acquiring nuclear arms," he told the Gulf Defence Conference held in Abu Dhabi.
Le Drian said it was the responsibility of countries to ensure that Iran's suspect nuclear programme "fails" in order to guarantee security for all.
The sanctions imposed by the United States and the European Union "appear to me to be the way to bring Iran to negotiate seriously," he added.
The International Energy Agency said on Wednesday that Western sanctions on Iran had slashed its oil export revenues by $40 billion in 2012 as production hit a three-decade low.
Iran insists its nuclear programme is for peaceful purposes.