"The real change I've made on this question, is that I haven't said the deposing of Bashar al-Assad is a prerequisite for everything," Macron said in an interview with several European newspapers, including Britain's Guardian, Spain's El Pais and Germany's Sueddeutsche Zeitung.
"Because no one has introduced me to his legitimate successor," said the French president, who took office last month.
His comments were met with dismay by the Syrian opposition.
"Shame on France, whose leader Emmanuel Macron does not see Bashar as its enemy or an enemy to humanity," tweeted Ahmed Ramadan, a member of the Syrian National Coalition, the main umbrella organisation of opposition groups.
"A tragic fall for morality and humanity," Ramadan added.
Khaled Khoja, another opposition figure, posted on Twitter: "Macron's statements are surprising, considering that France was among four countries in the core Friends of Syria group -- in addition to Britain, Turkey, and Qatar -- that had supported the departure of 'Chemical' Bashar."
Macron said he now saw two key priorities in Syria.
"My line is clear: one, a total fight against terrorist groups. They are our enemies... We need the cooperation of everyone to eradicate them, particularly Russia. Two: stability in Syria, because I don't want a failed state."
Macron said the international community had made a "collective error" in thinking the conflict could be solved "only with military force", adding: "My deep conviction is that we need a political and diplomatic roadmap."
But he repeated his warning that the use of chemical weapons and the violation of humanitarian corridors set up to deliver aid to desperate Syrian civilians were "red lines" and that France would be willing to act alone in response.
France was among Western nations pushing most vocally for Assad to go at the start of the conflict, which has since left more than 320,000 people dead and forced millions from their homes.