Born on December 3, 1955, in Bologna, he is the eldest son of Tommaso Casini, a literature teacher, local manager, and city secretary of the Christian Democracy (DC) party, and Mirella Vai, a librarian at the school district office. He has two sisters and a brother, Marco Casini, who has been Secretary General of the Central Apennine Basin Authority since September 30, 2022. After graduating from the Luigi Galvani high school in Bologna with a classical education, he graduated in law from the University of Bologna in 1979, while at the same time joining the national youth leadership of the DC.
He was first married to Roberta Lubich, with whom he had two daughters, Benedetta and Maria Carolina. After his consensual separation from Lubich in 1998 and subsequent divorce, Casini began a new relationship with Azzurra Caltagirone, daughter of Roman entrepreneur and publisher Francesco Gaetano Caltagirone, whom he married in a civil ceremony in 2007, separating in 2015. Caterina (2004) and Francesco (2008) were born from this union. In July 2016, the divorce between Pier Ferdinando Casini and Azzurra Caltagirone was announced. He lives in Rome, where he teaches Mediterranean geopolitics at LUMSA University.