Ahmed Moaz al-Khatib said in a written statement he had reached his limit after what he called two fruitless years of appealing to the international community for help in ending the nation's bloody civil war.
"All the destruction of Syria's infrastructure, the detention of tens of thousands of people, the forced flight of hundreds of thousands and other forms of suffering have been insufficient for the international community to take a decision to allow the people to defend themselves," Khatib said.
A spokesman for Khatib told al-Jazeera the decision to step down from Syria's National Coalition was officially announced after a meeting with an EU delegation "which resulted in achieving nothing."
The National Coalition has been recognized by the Arab League as the official representative of Syria.
Al-Jazeera described Khatib as a moderate Islamist and former clergyman who had been an independent dissident in Syria over the years. Khatib said he planned to continue his efforts with a greater freedom than he had while part of the National Coalition.