In 1981 she was appointed an investigating magistrate, and later public prosecutor at the Lugano district attorney's office. As public prosecutor, Del Ponte dealt with cases of money laundering, fraud, drug trafficking, arms smuggling, terrorism and espionage, often looking into the many international links forged in Switzerland's role as a global business centre.

It was during that period that she and Investigative Judge Giovanni Falcone uncovered the link between Swiss money launderers and the Italian drug trade in the so-called "pizza connection." Judge Falcone was killed by a large Mafia bomb. Del Ponte was more fortunate as the half a tonne of explosives planted in the foundations of her Palermo home were discovered in time for her to escape the attempted assassination unhurt. Falcone's death nurtured Del Ponte's resoluteness to fight organised crime. Her enemies in the Cosa Nostra call her "La Puttana" ("the whore"). She therefore became the first public figure in Switzerland to require round-the-clock protection and armour-plated car.