In 2023, she made her directorial debut with the black-and-white feminist comedy-drama There's Still Tomorrow, which received critical acclaim and became one of the highest-grossing films of all time in Italy.

At 19 she began studying as an actress at the "Teatro Blu" in Rome (the same theatre school that Kim Rossi Stuart, Gianmarco Tognazzi, Claudia Gerini, Stefania Rocca, and Claudio Santamaria, among others, have attended).

Other major performances of Cortellesi on television include the 2004 edition of the Sanremo Music Festival and the leading role in the TV movie Maria Montessori: Una vita per i bambini, a biography of Maria Montessori, for which Cortellesi received the "Maximo Award" at the Roma Fiction Fest.

In 2008, she was nominated for the David di Donatello award for Best Supporting Actress for her role in the movie Piano, solo by Riccardo Milani.

In 2019 she was filmed in the title role of Petra for the four-part Italian TV crime drama, broadcast from September 2020.