[1][2] Casellati is a long-time member of the liberal-conservative party Forza Italia and served as Undersecretary of Health and Justice in previous governments.

[12] The 2008 election featured a strong showing by Berlusconi's new party The People of Freedom and his centre-right coalition; Casellati was re-elected in the Senate and served as undersecretary for Justice from 12 May 2008 to 16 November 2011, when the conservative Prime Minister was forced to resign amid financial crisis and public protests.

However, on 15 September 2014 she was elected by the Parliament in joint session to the High Council of the Judiciary (CSM), where she remained as a member until returning to the Senate in 2018 with the revived Forza Italia.

[18][19] On 18 April 2018 she was given an exploratory mandate by President Sergio Mattarella to try and reconcile the issues between the centre-right coalition and the Five Star Movement (M5S), in order to break the post-election political deadlock and form a fully functional new government.

Casellati was strongly supported by the League's leader Matteo Salvini, who stated that it was a "true honor to propose her as the first female president".

Casellati gained a mere result of 382 votes,[25] far below the majority threshold of 505 required to be elected and even below the number of centre-right electors, due to more than 70 so-called "snipers" (Italian: franchi tiratori).

[28] On 22 October 2022, following the right-wing victory in the general election, Casellati was appointed Minister for Institutional Reforms in the government of Giorgia Meloni.

In late December 2022, Meloni announced that Casellati would meet with the opposition parties to officially begin the roadmap towards a constitutional reform to strengthen the powers of the Prime Minister.

[37][38] During the 2020 International Day Against Homophobia, she stated that "any type of sexual discrimination is something to be considered intolerable and shameful in a modern society.

"[41][42] On 15 March 2013, she presented a law for the abolition of the IMU, the real estate tax promoted by Mario Monti's technocratic government in 2011.