• Prime Minister of Syria Salah ad-Din -al-Bitar, 1912
  

In the course of the next two years, al-Bitar and Aflaq along with some other associates edited for a period a review entitled al-Tali`a (the vanguard). According to historian Hanna Batatu, this displayed more concern with social issues than with the national question, and the political orientation of the two young activists was closer to the Syrian Communist Party than to any of the other groups on the political scene in Damascus. They would become disillusioned with the Communists in 1936, after the Popular Front government came to power in France; although the French Communist Party was now part of the government, the colonial power's approach to its subject nations was not appreciably different. The Syrian party's stance in these circumstances did not impress the young nationalist activists.

In 1939, Aflaq and al-Bitar began to attract a small following of students, and in 1941, the pair issued leaflets agitating against French rule, using the title al-ihyaa' al-'arabi - "the Arab Resurrection". Their first use of the name al-ba'th al-'arabi, which has the same meaning, came some time later; it had already been adopted by Zaki al-Arsuzi, a nationalist activist from Iskandarun province in north - western Syria who had come to Damascus in the wake of his native area's annexation by Turkey.

On 24 October 1942 both al-Bitar and Aflaq resigned from their teaching positions, now determined to devote their full efforts to the political struggle. They slowly gained supporters, and in 1945 the first elected Bureau of the Arab Ba'th Movement was formed, including both of them. The following year, the organization gained a substantial number of new members when most of the former supporters of Zaki al-Arsuzi, led by Wahib al-Ghanim, joined it.

In 1947 the first party congress was held in Damascus, and al-Bitar was elected secretary general. Aflaq took the pre-eminent position of 'amid, sometimes translated as "doyen"; under the constitution adopted at the congress, this made him effective leader of the party, with sweeping powers within the organization.

In 1952 Syria's military dictator, Adib al-Shishakli, banned all political parties. Al-Bitar took refuge in neighboring Lebanon, along with Aflaq. There they came into contact with Akram al-Hawrani, a far more seasoned politician who had recently established the Arab Socialist Party and boasted a considerable following among the peasantry of the Hama region in central Syria as well as a valuable foothold in the military officer corps. The three politicians agreed to unite their parties, and co-operated in the overthrow of al-Shishakli in 1954, following which a congress ratified the merger of the two parties into the Arab Socialist Ba'th Party. The rules and constitution of al-Bitar and Aflaq's party were adopted unchanged. All three were elected to the party's new National Command, along with a supporter of al-Hawrani.

Following the overthrow of al-Shishakli, Syria held its first democratic elections in five years. Al-Bitar was elected as a deputy for Damascus, defeating the secretary general of the Syrian Social National Party, one of the Ba'th's bitterest ideological enemies. He became Minister for Foreign Affairs in 1956 and held the post until 1958. Along with other Ba'thists, he agitated in favor of the unification of Syria with Nasser's Egypt, and when unification took place in 1958 he became Minister for Guidance of the new United Arab Republic (UAR). Like many of the other Syrian politicians who had initially supported unification, he found the experience disenchanting, and resigned his position the following year.

When a right wing coup in Syria put an end to the UAR, al-Bitar was one of sixteen prominent politicians to sign a declaration in support of the secession. Al-Hawrani also signed, but al-Bitar was still known as a Ba'thist whereas al-Hawrani's secessionist position was well known. Much of the party's base was outraged by al-Bitar's action, although he quickly retracted his signature. The Ba'th splintered in the aftermath of the secession, with a large part of its base turning to Nasserism. Al-Bitar remained close to Aflaq, who retained the party leadership with a pro-reunification line, albeit a more cautious one than that of the Nasserists or the Arab Nationalist Movement (ANM), and indeed a more cautious one than much of the party's membership wished for.

In 1963, a military coup by pro-reunification officers removed the secessionist regime from power. The officers included many Ba'thists, but also initially Nasserists and other elements. They established a National Revolutionary Command Council (NCRC) as the supreme organ of power in the land, and this body offered al-Bitar the position of prime minister at the head of a coalition cabinet made up of the various pro-reunification forces. Al-Bitar took up the appointment, and was later appointed to the NCRC as well.

However, the military Ba'thists who had taken control were not in tune with Aflaq and al-Bitar. They were of a younger generation, and a more radical disposition, traits they shared with an increasingly influential element of the civilian party membership in both Syria and Iraq. Later that year, the radical elements gained control of the party at the Sixth National Party Congress. The Congress approved a far left program evidently inspired by Soviet socialism, and condemned what it termed "ideological notability" inside the party - an implicit attack on Aflaq and al-Bitar. The latter resigned the premiership, which passed to a military moderate Ba'thist officer, Amin Hafiz. Al-Bitar was restored to the position the following year when the ruling group decided to adopt a more conciliatory approach following massive riots in Hama, which the army had to suppress.

However, al-Bitar was clearly not in any sense in charge of Syria - rather, he was acting as the face of a regime with which he was ideologically and personally out of sympathy.

On 23 February 1966 a bloody coup d'état led by a left wing Ba'athist faction headed by Chief of Staff Salah Jadid, overthrew the Syrian Government. A late warning telegram of the coup d'état was sent from President Gamal Abdel Nasser to Nasim Al Safarjalani (The General Secretary of Presidential Council), on the early morning of the coup d'état. The coup sprung out of factional rivalry between Jadid's "regionalist" (qutri) camp of the Ba'ath Party, which promoted ambitions for a Greater Syria and the more traditionally pan-Arab, in power faction, called the "nationalist" (qawmi) fraction. Jadid's supporters were also seen as more radically left wing. Members of the party's other fractions fled; al-Bitar was captured and detained, along with other members of the party's historic leadership, in a government guest house. When the new rulers launched a purge in August that year, al-Bitar managed to make his escape and flee to Beirut. In 1969, al-Bitar, President Amin al-Hafiz, Nasim Al Safarjalani, Khaled Al Hakim and others were sentenced to death in absentia by a special military court headed by later Syrian Defense Minister, Mustafa Tlass, and Interim Syrian President and Vice President of Syria Abdul Halim Khaddam. In 1978 al-Bitar was pardoned by then President Hafiz al-Asad after the latter came to power in 1970. However, despite a brief return to Damascus he was not reconciled with al-Asad, and in 1978, after a meeting with him ended without agreement, he launched a press campaign against the Syrian government in power from his exile in Paris, attacking it in a new magazine which he entitled al-Ihyaa' al-'arabi in an echo of the name he and Aflaq had first adopted almost forty years earlier. He was also rumored to be in contact with Syrian opposition figures in Baghdad.

On 21 July 1980 Salah ad-Din al-Bitar was shot dead in Paris. The identity of his actual killer was never discovered, but it was reported that Hafiz al-Asad had ordered the assassination. At the time al-Bitar had reported to local authorities in France that he had repeatedly received death threats by mail and phone. He took personal measures by limiting his moves. In response to a personal request by Nasim Al Safarjalani, a colleague and a close friend, to leave France to a safe haven, he promised to do so.

On the morning of his assassination he received a phone call to meet a journalist at his newspaper al-Ihyaa' al-'arabi office. As he was exiting the elevator to enter his office, his assassin fired two shots to the back of his head. He reportedly died at the scene. The journalist meeting was a setup.

At the time of the assassination, al-Bitar was holding a diplomat passport issued by Yemen. The media initially reported the assassination as a Yemeni diplomat assassination only to later identify the victim as the Syrian Prime Minister.

al-Bitar was later buried in Baghdad, Iraq.