Hanegbi's political career began in 1979 when he was elected as the head of the Jerusalem students' union. He was then elected as head of the National Student Union of Israel in 1980.
In 1984 Hanegbi was appointed as an adviser to Foreign Minister Yitzhak Shamir, and in 1986 he was made head of Prime Minister Shamir's bureau. Hanegbi was elected for the first time as a member of the Knesset for the Likud Party in 1988. He served in the Israeli parliament for 22 consecutive years, until December 2010. During the 13th Knesset (1992-1996) Hanegbi chaired the economic committee.
In 1996 Hanegbi was appointed minister of health in Binyamin Netanyahu's government and later that same year he was appointed minister of justice. In 2001 Hanegbi was appointed minister of the environment in Ariel Sharon's government and for a few months he also held the position of minister of transportation. In February 2003 Hanegbi was appointed minister of public security in Ariel Sharon's second government.
In September 2004 Hanegbi was appointed by Prime Minister Sharon to be a minister in the prime minister's office in charge of Israel's intelligence services and the strategic dialogue between Israel and the United States. In November 2005 Hanegbi led Israel's delegation to Washington D.C. for strategic discussions with the U.S. administration on the region's political and security issues.
In 2006 Hanegbi was appointed Chairman of the Foreign Affairs and Defense committee, a role he filled until December 2010. In January 2012 Hanegbi was elected a Member of the 19th Knesset for the Likud party, and chaired the House Committee, the Defense Budget Committee and the Foreign Affairs and Defense Committee. In June 2014 Hanegbi was appointed as the Deputy Minister of Foreign Affairs. In June 2015, following Israel general elections, Hanegbi was appointed Chairman of The Foreign Affairs and Defense Committee, Chairman of the ruling party Likud faction and Chairman of PM Netanyahu's coalition.
Hanegbi served as a paratrooper in the Israel Defense forces and earned a B.A. in international relations from Hebrew University in Jerusalem. In 1994 Hanegbi received his L.L.B. from the Law School of the Hebrew University in Jerusalem and was accepted into the Israeli Bar Association.
Hanegbi is married to Randi and they have four children.