Mikati was born on 24 November 1955 and hails from a prominent Sunni Muslim family based in Tripoli. He graduated from the American University of Beirut in 1980 with a Master of Business Administration (MBA) degree. He also attended a summer school program held at Harvard and the French Business school INSEAD.

Mikati co-founded the telecommunications company Investcom with his brother Taha in 1982. He sold the company in June 2006 to South Africa's MTN Group for $5.5 billion. In April 2015, Forbes estimated his net worth at $3.3 billion, making him the richest man in Lebanon.

After being appointed Minister of Public Works and Transport on 4 December 1998, Mikati was elected to the Lebanese parliament from his hometown of Tripoli in 2000, outpolling Omar Karami, who was elected from the same multimember constituency. As a parliamentarian, Mikati retained his cabinet position and developed a reputation as a moderately pro-Syrian Politician with a normal relationship with Syrian President Bashar Assad. Later Mikati was made transportation minister and became an ally of then Lebanese President Emile Lahoud, supporting the extension of his term in 2004.

Mikati's immediate priority was to prepare Lebanon for crucial parliamentary elections, which were scheduled to be held by 31 May 2005. Constitutionally, a government must be in place to call for an election, and opposition politicians had accused President Lahoud and former prime minister Karami of stalling the formation of a government in order to thwart the elections, which anti-Syrian parties believed they could win. Mikati's government succeeded in organizing the election, which saw the opposition (by that time known as the 14 March Movement) win 72 out of the 128 seats in the National Assembly.

On 24 January 2011, the March 8 alliance, specifically Hezbollah, Michel Aoun and Walid Jumblatt, nominated Mikati to become prime minister. Mikati succeeded Saad Hariri, whose government was brought down by the resignation of ten of the alliance's ministers and one presidential appointee on 12 January 2011, resulting from the collapse of the Saudi-Syrian initiative to reach a compromise on the Special Tribunal for Lebanon. On 25 January, 68 members of the parliament of Lebanon voted in favor of nominating Mikati for Prime Minister. President of Lebanon Michel Suleiman then invited Mikati to head a new Lebanese government. The process of government formation lasted for five months due to serious disagreements between Leaders. On 13 June 2011, Mikati became the Prime Minister of Lebanon for the second time.

On 13 June, Mikati announced the formation of the government and stated that it would begin by "liberating land that remains under the occupation of the Israeli enemy". On 22 March 2013, Mikati resigned from office, due to "intensifying pressure between the pro-Assad and anti-Assad camps" and the Lebanese President accepted his resignation on 23 March 2013. On 6 April 2013, Tammam Salam was tasked to form a new government.