Originally active within the Communist Party, Orlando became a founding member of the PD in 2007, and has since been regarded as a senior representative of its left-wing.

Orlando first became a member of the Chamber of Deputies in the 2006 Italian general election, representing the Liguria constituency.

[5] In 2009, he was made the head of the justice forum of the PD, under the leadership of chairman Pier Luigi Bersani.

[9] On 13 February 2014, following tensions with his left-wing rival and new secretary of the Democratic Party, Matteo Renzi, Letta announced he would resign as prime minister the following day.

[17] By June 2017, after more than two years of debate, Italy's parliament approved a contested reform of the justice system proposed by Orlando and aimed at making it more difficult for criminals to avoid conviction.

[24] When Italy held the rotating presidency of the G20 in 2021, Orlando chaired the meetings of the group's ministers of labour.