On 31 December 2012, Guerini resigned from his post, in order to present his candidacy for the upcoming parliamentary election in February 2013, in compliance with the eligibility conditions.

[9] After winning the special primaries organized by the Democratic Party, Guerini was included in the list of candidates for the Lombardy 3 constituency of the Chamber of Deputies and was finally elected.

In August 2019 tensions grew within the populist government, leading to the issuing of a motion of no-confidence on Prime Minister Giuseppe Conte by the League.

[11] After Conte's resignation, the national board of the PD officially opened to the possibility of forming a new cabinet in a coalition with the M5S,[12] based on pro-Europeanism, green economy, sustainable development, fight against economic inequality and a new immigration policy.

[19] Shortly after taking office in 2019, Guerini announced that the Italian government would press ahead with an investment program for Lockheed Martin F-35 Lightning II fighter jets.

[20] In 2021, he backed the involvement of shipbuilder Fincantieri in the sale of Leonardo’s OTO Melara and Whitehead Sistemi Subacquei units, in an effort to safeguard what the Italian government considers strategic assets.

[27] On 11 February 2022, amid the Russo-Ukrainian crisis, during a meeting in Riga with his Latvian counterpart, Artis Pabriks, Guerini called for "a constructive dialogue" with Russia to ease tensions.

[31] On 16 March, in response to growing tensions with Russia, the Chamber of Deputies voted to increase military budget to 2% of GDP, a move firmly advocated by Guerini himself.

[32] On 19 March, Alexei Paramonov of the Russian Ministry for Foreign Affairs attacked Guerini, describing him as a war hawk and as an "inspirer of an anti-Russian campaign".