He entered politics in 1976 as legal adviser to Christian Democratic reformer Piersanti Mattarella, who became president of the Sicilian Region in 1978.

[3] From 1985-1990 he was elected mayor of Palermo, and received many threats as a result of his open opposition to the power of the Mafia in the city.

Leoluca Orlando attacked harshly Giovanni Falcone accusing him of having "kept closed in the drawers" a series of documents concerning the excellent mafia crimes.

[4] The charges were also addressed to the judge Roberto Scarpinato and the prosecutor Pietro Giammanco, believed to be close to Andreotti.

Recipients of the bribe, according to the repentant, were the Mayor Leoluca Orlando and the councilor Vincenzo Inzerillo, who at the time of the facts was in prison for 16 months for mafia.

After the dissolution of the DC, he founded a popular movement called The Network ("La Rete"), which in 1999 joined with Romano Prodi's Democrats.

He subsequently joined the Italy of Values of Antonio Di Pietro with whom he was elected at the Italian Chamber of Deputies.

[17][18][19] In June 2018, in defiance of orders from the Italian government, Orlando stated that he would allow the Aquarius, bearing 629 migrants rescued off the coast of Libya, to dock in Palermo.

[24] Since 2000, he has been the President of the "Sicilian Renaissance Institute" a non-profit organization dealing with the promotion of economy and culture of lawfulness and Human rights.

[25] In 2023 he established Fondazione Mosaico, a non-profit dedicated to promoting cultural understanding, tolerance, and human rights.