In 1958 he was elected to the Knesset for Mapai. He was chairman of the Knesset House Committee, member of the Constitution, Law and Justice Committee, chairman of the Subcommittee on Constitutional Affairs, and member and Chairman of the Foreign Affairs and Defense Committee. He was involved in the passing of the Law on Inquiry Commissions and the Basic Law: the Government, as well as in attempts to pass basic laws on Legislation and Civil Rights, sections of which were later passed in the Basic Laws on Human Dignity and Freedom and Freedom of Occupation. From 1965 to 1966 he was Minister of Industry and Trade.
In 1974 he became Minister of Justice, a position he held until the 1977 "Upheaval". When Meir Shamgar was made a Judge, Zadok appointed Aharon Barak as Attorney-General. With the assistance of these advisors, he passed the Basic Law: the Military and the Basic Law: the State Economy. Towards the end of his tenure at the Ministry of Justice, the translation of the Mandatory Criminal Law Ordinance was completed, and a new and integrated Penal Code was formulated. From 1974 to 1977 he was also the first secular Minister of Religious Affairs.
His tenure as Minister of Justice saw investigations of senior figures in the Israeli economy and Israeli politics, including the Yadlin affair, the Dollar Account affair and the suicide of Avraham Ofer. Zadok stood by Barak when he decided to prosecute, and refused calls from within the Labor Party to intervene in the investigation. He opposed the Israeli settlements but allowed them to reside in IDF camps, as a compromise. He was among the initiators of the sarcastically named "Brilliant trick", in which Prime Minister Yitzhak Rabin sacked the National Religious Party ministers, a move which eventually collapsed the government. In 1978, he retired from political life.
He was a member of many public committees, including the Shamgar Commission, which considered the definition of the role and appointment of the Attorney-General, and he chaired committees that considered the regulation of police activity, the religious councils and the press. In 1991, he was one of the founders of the Israel Democracy Institute and served as the first Chairman of its Board of Directors. In 1993, he was made President of the Press Council. He held liberal views that ruled out government intervention in the free press. In 1999 he was last on One Israel's list for the fifteenth Knesset.