In 2004, she was elected Dean of the III Regional Council of the Medical Colleges of Peru, a position she left to be sworn in as Minister of Health in February of the same year.

[5] At the end of 2005, Mazzetti headed the meeting of Ministers of Health of the Andean Community, where the problem of bird flu and its possible arrival in South America were discussed.

In January 2006, Mazzetti faced a new strike for payments that the Labor sector could not make to EsSalud doctors, thus paralyzing health services.

[6] On 28 July 2006, Mazzetti was sworn in as Minister of the Interior at the start of the second presidency of Alan García, becoming the first woman to assume the position in Peruvian history.

Upon taking the oath of office, she headed to the headquarters of the Ministry of the Interior, where she received from the hands of the former Minister Rómulo Pizarro, the portfolio dispatch.

Into February 2007, she faced a series of criticisms for the acquisition (via public bidding) of 469 trucks for the National Police of Peru, which prices were considered by the media as overvalued.

[10] On 15 July 2020, President Martín Vizcarra reshuffled his cabinet under the leadership of Pedro Cateriano as Prime Minister of Peru, thus appointing Mazzetti to the Ministry of Health for a second time in her career.

[11][12] Upon the rejection of confidence against the newly recomposed cabinet, Vizcarra proposed Mazzetti to take the office of Prime Minister of Peru and succeed Cateriano, which she did not accept.

[15] Mazzetti resigned as Minister of Health upon the revelation of former president Martín Vizcarra's secret COVID-19 vaccination with Sinopharm Group in September 2020 while Peruvians struggled due to the COVID-19 pandemic, with her knowledge.