Al-Quwatli became politically active early on when he joined al-Fatat in 1910. Al-Fatat was a secret society, which called for the liberation of the Arabs.  His activism, together with a number of al-Fatat’s members, resulted in them being placed under arrest and subjected to torture and humiliation at the Khaled Basha prison in Damascus, before they were sentenced to death. However, the Arab revolt led by King Hussein against the Ottomans yielded the arrest of a number of Ottoman army officers and troops and the detainees were swapped for the release of al-Quwatli and his companions. 
Following the departure of Ottomans from Syria, al-Quwatli established the Independence Party, the first party which undertook the responsibility of educating the people and preparing it for the struggle against the French colonizer, which occupied Syria after the Ottoman retreat. In 1920, a sentence was issued forcing al-Quwatli and his companions to leave for Egypt and other Arab countries and they could not to return until 1930 after they had been pardoned from death row. Al-Quwatli participated in the Arab nationalist conference held by a number of Arab liberals in Jerusalem in 1931 in order to lay down the historical pact that the Arabs needed to abide by in the next stage.  In 1932, he was a founding member of the National Bloc which later became a national party calling for the independence of Syria. When Jamil Mardam Bey formed the first government in the independence era, he appointed al-Quwatli as Minister of both Finance and Defense. 
In 1937, while al-Quwatli was on pilgrimage in Saudi Arabia, Mardam Bey held a series of meetings with the French that concluded an agreement to carry on the cooperation between the two countries. This agreement was challenged by ministers and MPs, raising the ire of al-Quwatli in particular who responded by resigning from the ministry. Al-Quwatli maintained his parliamentary post and was re-elected in 1938 as Speaker of Parliament. Three years later, he was voted leader of the National Bloc, in succession to Ibrahim Hanano. Al-Quwatli led the electoral battle with a unified list after the death of French-appointed President Taj al-Din Hasani and was voted President on August 17 1943, moving Syria to a new era of internal reforms on economic, political, social and urban levels. Syria made the transition towards liberty and independence and garnered international recognition from all countries around the world, except France. 
In 1945, al-Quwatli met British Prime Minister Winston Churchill and the two held lengthy discussions on the need to reach an understanding with France but al-Quwatli refused to acknowledge any rights for the French in Syria. When the Big Four conference was held in the presence of Roosevelt, Churchill and Stalin to approve the UN Charter, the US addressed invites to the nations to attend the conference, excluding Syria and Lebanon, upon the request of France. However, al-Quwatli kept on mediating with foreign and Arab countries until finally Syria and Lebanon were invited to join and became official members of the UN before the withdrawal of foreign troops from Syria on April 17, 1946.
In 1949, the Syrians were struck by the coup conducted by Chief of Staff Hussni Al-Zaim, which resulted in the detention of al-Quwatli and his ministers. Al-Quwatli was released after a while and was placed under house arrest until he left for Egypt. Voices were then raised in Syria demanding his return, so he returned, once again, as a presidential candidate. Al-Quwatli kept on fantasizing about the Arab unity until his dream finally came true upon the birth of the United Arab Republic. 
Chairing a Syrian delegation, al-Quwatli headed for Egypt to work out the union between Egypt and Syria with President Gamal Abdul Nasser. The United Arab Republic was thus born and al-Quwatli waived his position in favor of the union, paving way for the election of Abdul Nasser as President of the United Arab Republic. However, the UAR did not last long and the two countries split in September 1961. Following the Baath coup of March 8, 1963, al-Quwatli’s properties were confiscated so he left for Beirut and retired from politics. He continued to support Gamal Abdul Nasser until he died on June 30, 1967 and was laid to rest in Bab el-Saghir Cemetery in Damascus.