He served as mayor of Saigon twice, and was the Prime Minister from November 1964 – January 1965, and from May–August 1969. He also served as vice president under President Nguyễn Văn Thiệu.
During the rule of Ngô Đình Diệm, Hương was jailed in 1960 for signing the Caravelle Manifesto that criticised Diệm. However, after Diệm was overthrown and assassinated in 1963, Hương gave a scathing analysis of the coup generals' action. He stated that "The top generals who decided to murder Diệm and his brother were scared to death. The generals knew very well that having no talent, no moral virtues, no political support whatsoever, they could not prevent a spectacular comeback of the president and Mr. Nhu if they were alive."
On 26 September 1964, and due to US pressure, General Nguyễn Khánh and the senior officers in his military junta created a semblance of civilian rule by forming the High National Council (HNC), an appointed advisory body akin to a legislature.
The HNC, selected the aging civilian politician Phan Khắc Sửu as chief of state, and Sửu selected Hương as prime minister, a position that had greater power. However, Khánh and the senior generals retained the real power. At the time, both Saigon and Washington were planning a large-scale bombing campaign against North Vietnam in an attempt to deter communist aggression, but were waiting for stability in the south before starting the air strikes.
In January 1965, Hương introduced a series of measures to intensify the anti-communist war effort by expanding military expenditure using aid money and equipment from the Americans, and increasing the size of the armed forces by widening the terms of conscription. This provoked widespread anti-Hương demonstrations and riots across the country, mainly from conscription-aged students and pro-negotiations Buddhists. Reliant on Buddhist support, Khánh did little to try to contain the protests. Khánh then decided to have the armed forces take over the government. On 27 January, Khánh removed Hương in a bloodless putsch with the support of Thi and Ky. He promised to leave politics once the situation was stabilized and hand over power to a civilian body. It was believed that some of the officers supported Khánh's increased power so that it would give him an opportunity to fail and be removed permanently. Khánh persisted with the facade of civilian government by retaining figurehead chief of state Phan Khắc Sửu and making economics professor Nguyễn Xuân Oánh the caretaker prime minister.
Khánh's deposal of the prime minister nullified a counter-plot involving Hương that had developed during the civil disorders that forced him from office. In an attempt to pre-empt his deposal, Hương had backed a plot led by some Đại Việt-oriented Catholic officers reported to include Generals Thieu and Nguyễn Hữu Có. They planned to remove Khánh and bring Khiem back from Washington. The US Embassy in Saigon was privately supportive of the aim, but was not ready to fully back the move as they regarded it as poorly thought out and potentially a political embarrassment due to the need to use an American plane to transport some plotters, including Khiem, between Saigon and Washington. As a result, the Deputy Ambassador U. Alexis Johnson only promised asylum for Hương if necessary.
Khánh's deposal of Hương further heightened American opposition to him and fears that his reliance on Buddhist support would result in his not taking a hardline position against the communists. Aware that US support for him was further ebbing away, Khánh tried to initiate peace negotiations with the Việt Cộng, but he only managed an exchange of letters and was yet to organize any meetings or negotiations before he was overthrown. In the meantime, this only intensified US efforts to engineer a coup, and many of Khánh’s colleagues—mostly Catholic Đại Việt supporters—had by then privately concluded that he was set to pursue a deal with the communists.
Many of whom felt that Khánh thought of himself as the "Sihanouk of Vietnam"; the Cambodian monarch had managed to avoid the Cold War for the time being by shunning both communist and anti-communist blocs. During the first half of February, suspicions and evidence against Khánh began to solidify, an example being his order to release the wife of communist leader Huỳnh Tấn Phát from jail. Taylor's superiors in Washington began to align with his view, giving him more scope to agitate for a coup.
In the South Vietnamese presidential election, 1967, Khánh finished fourth with 474,100 votes (10.0%).
On 21 April 1975, Thiệu resigned and handed the presidency to Hương. On 28 April 1975, after one week as president, Trần Văn Hương resigned and handed power over to General Dương Văn Minh, who presided over the surrender of the government two days later.
Trần Văn Hương was placed under house arrest by the communist regime. When deemed adequately reformed in 1977, his civil rights were restored but he declined. Instead, he asked for all officials of the ARVN to be released from prison before he would take his place among the freed. His request was ignored. The former president died quietly in his own home in 1982.