With an independent nature and uninterested in traditional academic ideas and exercises, he was expelled two years later. Along with other painters, including Federico Rossano and Marco De Gregorio, he initially devoted himself to plein-air landscapes in the regions of Portici, Naples, and Barletta. In 1866 he travelled to Florence, drawn to the work of the Macchiaioli, then continued his travels around Italy, visiting Naples, Palermo, Rome, Florence, Venice, Turin and finally Barletta to bid good-bye to his family before leaving for Paris in 1867. There he soon met the most successful contemporary painters, Ernest Meissonier and Jean-Léon Gérôme who introduced him to the leading dealers and, two years later, married the Parisian Léontine Lucile Gruvelle, who greatly influenced her husband's social and artistic choices.

In 1869, he exhibited for the first time at the Salon, but his slavish imitation of his Parisian colleagues infuriated Ceccioni, who reminded him that his talent needed to be expressed more individually. This criticism propelled De Nittis into reconsidering his artistic direction and to his first great public success, at the 1872 Salon with the canvas A Road from Brindisi to Barletta. In 1874, he received further praise for How Cold!, in which he applied his refined technique to a portrayal of young Parisian ladies, a theme he integrated with his landscape painting, earning the nickname peintre des Parisiennes. He reached the peak of his fame at the exhibition of 1874, held in the studio of the photographer Nadar and commonly referred to as the first Impressionist exhibition.

The Paris International Exhibition, in 1878 was something of a triumph for the thirty-two year old painter, with one of his works, The Ruins of the Tuileries (originally titled Place du Carousel), being purchased by the government for the Luxembourg Museum, receiving as an exceptional distinction for someone so young, an appointment as a chevalier of the Legion of Honour.

The influences on De Nittis included both the Macchiaioli and the Impressionists, but his style could never be firmly categorised. His death from a sudden cerebral stroke in 1884, at the age of thirty-seven, came as shock to his many friends and contemporaries.

Professor Fausto Minervini has proposed a date circa 1867 from a photograph; it may be earlier. The subject is surely a young Italian woman, from her rather severe black dress and small brooch perhaps a school mistress or governess (the two most likely occupations for a respectable young woman from the bourgeoisie). Its direct and intimate character suggests she was well-known to the artist but nothing else is known before it appeared at a provincial auction in England.