Quang's campaign saw widespread demonstrations against the government of President Ngô Đình Diệm, including the self-immolation of at least five Buddhist monks led to a military coup in which Diệm and Nhu were deposed on 1 November 1963 and assassinated the following day.
In his early days, Quang went to Ceylon to further his Buddhist studies. When he returned, he participated in anti-French activities, calling for the independence of Vietnam. A declassified French Sûreté report showed that Quang joined the Indochinese Communist Party in 1949, a fact that former SRV Deputy Prime Minister Tố Hữu confirmed in 2000.
In 1963, Vesak (the birthday of Gautama Buddha) fell on 8 May. The Buddhists of Huế had prepared celebrations for the occasion, including the display of the Buddhist flag. The government cited a rarely enforced regulation prohibiting the display of religious flags, banning it. This occurred despite the non-enforcement of the regulation on a Catholic event celebrating the fifth anniversary of Ngô Đình Thục as Archbishop of Huế less than a month earlier. The Buddhists defied the ban and held a demonstration, congregating at the radio station, expecting to hear an address by Quang, but the authorities canceled the speech and opened fire on the crowd, killing 9 people.
On 10 May, Buddhists campaigned for religious equality, compensation for the victims, punishment for those responsible, and the right to fly the Buddhist flag. Quang urged the demonstrators to not allow the Việt Cộng to exploit the unrest and exhorted a strategy of passive resistance. As the crisis deepened, however, he traveled to the capital of Saigon for negotiations and further protests after the self-immolation of Thích Quảng Đức on 11 June. Prior to the 21 August Xá Lợi Pagoda raids engineered by Nhu's secret police and special forces, he sought refuge at the U.S. Embassy in Saigon. He was accepted by U.S. Ambassador Henry Cabot Lodge, Jr., who refused to hand him to Nhu's forces after they had ransacked pagodas, fired on civilians and beaten monks and nuns. In Huế, thirty people died as they attempted to protect their pagodas from Nhu's men.
Following the coup on 1 November 1963, which removed Diệm and Nhu from power, it was reported that the military junta wanted Thích Trí Quang to be a part of the new cabinet, but the U.S. State Department recommended against this. After the 1964 coup by General Nguyễn Khánh, which deposed the Dương Văn Minh junta, Khánh had Captain Nguyễn Văn Nhung, the bodyguard of Minh and executioner of Diệm and Nhu, executed. This generated rumours that pro-Diệm politicians would be restored to power and prompted Quang to cancel a planned pilgrimage to India to organise further demonstrations. In 1966, demonstrations occurred when anti-Diệm General Nguyễn Chánh Thi, the commander of central Vietnam, was stripped of his position by Prime Minister Nguyễn Cao Kỳ. Kỳ had Quang arrested and placed him under house arrest in Saigon. When the communists overran South Vietnam in the fall of Saigon in April 1975, Quang was again placed under house arrest.