Ghannouchi was a member of the Tunisian parliament for the Democratic Constitutional Rally. He was Minister of Finance from 1989 to 1992. From 1992 to 1999, he served as Minister of International Co-operation and Foreign Investment, and from 1999 to 2011 he was the Prime Minister of Tunisia, making him the longest serving prime minister since the proclamation of independence, surpassing his predecessor Hamed Karoui. After the fall of President Zine El Abidine Ben Ali on 14 January 2011 in the wake of the 2010–2011 Tunisian uprising, he was the self-proclaimed acting President of the country for a few hours starting on 14 January 2011, under Article 56 of the Constitution of Tunisia. He remained Prime Minister for six weeks before stepping down.
In a 2006 diplomatic cable from the United States that was leaked by WikiLeaks during the United States diplomatic cables leak, Ghannouchi was described as being generally popular among the population of Tunisia. Ghannouchi was seen as a respected technocrat by US diplomats in early 2010, with a cable stating, "Prime Minister Ghannouchi, the respected,, pragmatic, and apolitical technocrat, has served in his post since 1999 and with his reappointment appears set to surpass longevity records for senior officials since Tunisia's independence in 1956. Tunis oddsmakers had expected Ghannouchi, reportedly tired after a decade on the job, to move on, but it appears Ben Ali has come to view him as indispensable." Passport, a blog by Foreign Policy, gave a different view of Ghannouchi, saying he "is not necessarily any more popular than Ben Ali, though he's not nearly as tainted by the lurid tales of corruption and excess that so damaged the ruling family. But Tunisians certainly don't respect the prime minister; they call him 'Mr. Oui Oui' because he's always saying yes to Ben Ali".
Role following 2010–2011 Tunisian uprising
On 14 January 2011, before Ben Ali had fled the country during the Tunisian Revolution, Ghannouchi announced that Ben Ali had called for parliamentary elections in six months, dismissed the government, and asked him to form a new government. During the evening, Ghannouchi announced that he was taking temporary control of the country on state television. Ghannouchi promised to begin discussing political and economic reforms the next day. Ghannouchi said he would hold new elections within sixty days, as required by the Tunisian Constitution. On January 15, The Economist reported that some protesters were calling for Ghannouchi to step down. On that same day, it was announced that CongressSpeaker Fouad Mebazaa was taking the post of Acting President of Tunisia. Al Jazeera claimed that some lawyers disagreed with Ghannouchi's claim to power, interpreting the constitution differently, in particular referring to Article 57. Afterwards he resumed as Prime Minister and formed a new national unity government that included members of opposition parties, civil society representatives, and even a blogger, Slim Amamou, who only a week previous had been imprisoned by the regime of the deposed President. Ghannouchi resigned his membership of the RCD on 18 January. His resignation was followed by similar action by the other RCD members within the government; but on 27 January, Ghannouchi carried out a major reshuffle of the government to remove all former RCD members other than himself. After a new wave of protests, Ghannouchi resigned as PM on 27 February 2011. The current whereabouts of Ghannounchi to this day are unknown, but it is likely Ghannounchi is still residing in Tunisia with his family.