Quwatli entered Syrian politics in the 1930s as a member of the National Bloc, an Arab group that led the opposition to French rule. Quwatli assumed leadership of the movement in 1940. His tolerance for the corruption of his associates helped keep him in power. The National Bloc remained the dominant expression of Syrian nationalism, and, when Syria became independent in 1943, the bloc helped elect Quwatli president. His major concern was to conclude a treaty with France, which had exercised control over Syria for more than 20 years. This was accomplished with British help, and by 1946 all foreign troops had left. In 1947 Quwatli enacted an amendment that removed a one-term limit from the constitution, and he was reelected in 1948.

Because of the Israeli victory over Arab forces (1948), as well as dissatisfaction with Quwatli's rule, he was overthrown by a military coup in March 1949. After a short imprisonment, he went into exile in Egypt, waiting for a chance to regain his position, while a series of coups paralyzed Syrian political life. Free elections once again took place in 1955, and Quwatli, at the head of the National Party (the successor to the National Bloc), was elected president. By then his post was largely ceremonial, however, and he had little influence on Syria's domestic politics thereafter.