His father Tommaso was an Italian literature teacher and a local leader of the Christian Democracy (DC), while his mother Mirella was a librarian.

In 1980, Casini was elected municipal councillor in his hometown, Bologna, a traditional stronghold of the Italian Communist Party (PCI), the DC' historic rival.

During his first years as deputy, he became a close advisor of Arnaldo Forlani, one of the most prominent leaders of the DC, head of the conservative faction of the party.

In the 1987 Italian general election, he was re-elected with more than 52,000 votes and appointed vice president of the so-called "Massacres Commission", focused on the terrorist attacks perpetrated in Italy during the Years of Lead.

The party suffered a serious consensus crisis, and Casini, together with Clemente Mastella, took positions against Martinazzoli, leaning towards an alliance with Forza Italia (FI), a new conservative political party founded by the media magnate Silvio Berlusconi, the Italian Social Movement (MSI) of Gianfranco Fini and Umberto Bossi's Northern League (LN), aiming at forming a centre-right coalition in opposition to the centre-left one built around the post-communist Democratic Party of the Left (PDS).

In the 1996 Italian general election, Casini's CDC formed a joint list with Rocco Buttiglione's United Christian Democrats (CDU).

On 14 November 2002, Casini was the protagonist of a historical event that never happened before: the visit of a Pope to Palazzo Montecitorio, the seat of the Chamber of Deputies.

Casini and Senate's president, Marcello Pera, invited Pope John Paul II to the house.

[12][13] On 28 January 2006, Casini was elected president of the Christian Democratic International (IDC), succeeding José María Aznar, a position that he held until July 2015.

[17][18] Casini long criticised the PdL for not being "Catholic" enough, particularly criticising Berlusconi, who once spoke of "anarchy of values" in describing the catch-all nature of the PdL,[19] and Gianfranco Fini, who was known for his social-liberal stance on stem-cell research, abortion and right-to-die issues,[20] and explicitly wooed the "Christian democrats of the PD" to join him.

In 2013, Casini supported the grand coalition cabinet of Enrico Letta and, in February 2014, the new centre-left government of Matteo Renzi.

However, some UdC splinters, notably including Casini and minister Gian Luca Galletti, launched "Centrists for Italy" and confirmed their alliance with the Angelino Alfano's New Centre-Right, in support of the centre to centre-left cabinet.

[30][31][32] In the 2018 Italian general election, the CP obtained a mere 0.5%, but Casini was re-elected to the Senate with nearly 122,000 votes from a single-seat constituency in Bologna, thanks to the decisive support of the PD.

[33] In the 2022 Italian presidential election, Casini was considered one of the most reliable candidates[34][35] but later asked to rule out his name and vote for the incumbent president Sergio Mattarella.