Matilde Serao was born in Patras, Greece, to an Italian father who had emigrated after the tumultuous political events of 1848, and a Greek mother. The family returned to Italy when she was a small child and she spent nearly her entire life in Naples. She worked in the telegraph office and as a teacher, and would later describe those years in a book of short stories called Leggende Napolitane (1881). Her first novel, Fantasia (1883), established her as a writer. She spent the years between 1880 and 1886 in Rome, where she published the next five volumes of stories and novels, including Cuore infermo (1881), Fior di passione (1883), La conquista di Roma (1885), La Virtù di checchina (1884), and Piccole anime (1883).
In 1885, she married Edoardo Scarfoglio, with whom she had four sons. Together, the couple founded a daily newspaper, Il Corriere di Roma, and two other periodicals. After separating from her husband, she returned to Naples and became the first woman in Italy to start her own newspapers, La Settimana and Il Giorno. She continued to write fiction, most of it dealing with lower-middle-class Neapolitan life, and produced a total of about 40 works in her career.