After completing his yeshiva studies, Deri was appointed secretary of the Haredi settlement of Ma'ale Amos, and joined the Gush Etzion Regional Council.

[7] During 1985, he served as an assistant to Interior Minister, Yitzhak Peretz, and at the end of the same year he was appointed to the role of the Secretary General of Shas.

Upon completing his military service at the age of 27, and after the elections for the 12th Knesset, he was appointed interior minister in the government of Yitzhak Shamir.

At the end, Yitzhak Shamir, Likud chairman, established a government of Likud–Right–Haredis, where Deri continued to serve as Interior Minister.

However, on 28 December 2014, Channel 2 released video footage in which Ovadia Yosef, the founder of Shas, attacked Deri, calling him a wicked man and a thief.

Despite his resignation from the Knesset, Deri headed the Shas list for the March 2015 election, and was subsequently appointed Ministry of the Economy and Minister for the Development of the Negev and Galilee in the new government.

[15] On 17 April 2020, a senior Likud Minister, speaking unattributably, told Al-Monitor that Deri was mediating the political coalition talks between Netanyahu and leader of the opposition Blue and White alliance Benny Gantz.

[16] It was also reported Deri "might even be open to a new alliance with Blue and White — now that its anti-clerical component, Yair Lapid, quit the party and went his own way", and would only commit to remaining with Netanyahu's coalition until the next election.

[16] On 20 November 2018, Israeli police ended a criminal investigation into Deri with a recommendation to state prosecutors that he be indicted for "committing fraud, breach of trust, obstructing court proceedings, money laundering, and tax offenses.

"[17] In 2019, this recommendation was adopted in full by the state prosecutor, Shai Nitzan, but in 2021 the attorney general of Israel, Avichai Mandelblit, dropped all the charges except the tax offenses.

[18] Deri continued to serve as Interior Minister, and after losing the ministry with the formation of the thirty-sixth government of Israel, as an MK and chair of the Shas party.

[22][23] On 2 February 2022, Deri gave a speech in which he accused his prosecution of being motivated by his Moroccan heritage, and expressed his intent to remain as leader of Shas.

[26] On 18 January 2023, the Supreme Court of Israel ruled that Deri was not allowed to hold a position as a cabinet minister due to his conviction for tax offenses.

[1] His older brother, Yehuda Deri, was the Chief Rabbi and Av Beit Din of the city of Be'er Sheva.