He was born in Rome to Paolo, a tailor from Narni, and Domenica Cinti from Terni. He showed such precocious artistic talent that, at just twelve years old, he was admitted to the Academy of Fine Arts in Naples, where he studied under Domenico Morelli, Filippo Palizzi, and Stanislao Lista. He was also close friends with sculptor Vincenzo Gemito, who was the same age, and with whom he shared a poor and difficult youth—a theme that influenced both their artistic work.

As early as 1871, two of his works exhibited at the Neapolitan "Promotrice" were purchased by foreign patrons, both painters: "For a Flower" by Canadian-American painter François B. De Blois and "The Last Medicine!" by Frenchman Felix de Lapommeraye. In 1872, he traveled to Venice, where he was deeply impressed by Venetian painting. Three years later, he completed his academic studies, and in 1883 he moved to Rome where he opened his own studio. He embraced the artistic movement of Verismo, dedicating himself to portraiture and anecdotal genre painting.

In 1877, he moved to Paris for several months, working for art dealers Adolphe Goupil and Hendrik Willem Mesdag. There he met Degas and Manet and became friends with Sargent, who considered him "the best living painter." He also met Ernest Meissonier and Jean-Léon Gérôme. He also visited London at Sargent's invitation, where his painting continued to achieve success.

He returned to Naples and went back to Paris in 1877. In 1878, he returned to Naples, suffering from illness and deep depressive episodes that, in 1879, led to his admission to a nursing home until 1883, when he decided to move permanently to Rome, where he could count on financial support from his artist friends. In Rome, he met "Aurelia" who, besides posing as his model, became his life companion.

In 1885, he signed a contract with Dutch patron Mesdag, who regularly sent him money in exchange for paintings and drawings (approximately 150 works) that the dealer would keep for himself (today they are in the museum named after him) and sell the rest. Between 1901 and 1902, he was in England, where he went to execute some portraits of high society, encouraged by American painter John Singer Sargent. He would return to England and Ireland between 1907 and 1908. He also had a contract with dealer Messinger (he would work for him until 1911) and then with patron and collector Fernand du Chêne de Vère, who hosted him at his residence "Villa Jacobini" (Casal Romito) in Frascati, where he stayed for 11 years, until 1918.

He exhibited in Venice in 1914 and 1920, when the XXII Biennale dedicated a solo exhibition to him. In 1928, he exhibited at the Sforza Castle in Milan, and in 1929 he was admitted to the Academy of Italy. He joined the Fascist movement and gave a self-portrait to Mussolini, who in turn was tempted to donate it to Hermann Goering on the occasion of the Nazi hierarch's 50th birthday on January 12, 1943 (he was convinced not to do so by his son-in-law Ciano).

Despite his two stays in Paris, Antonio Mancini remained deeply disconnected from the most current trends in French painting of the time, preferring a strong connection to Italian nineteenth-century naturalism. Popular life, often marked by hints of sadness, characterizes his early works such as "il Prevetariello" (The Little Priest), "lo Scugnizzo" (The Street Urchin) at The Hague's Mesdag Museum, and "Self-Portrait" at the National Gallery in London. His later works are dedicated to portraits of ladies, self-portraits, and strange figures in fanciful disguises executed in a more agitated manner, with vivid flashes of light, placed on the canvas in clumps of violent color and bright drips. His further experimentation (incorporating pieces of glass, fabrics, and other materials into the painting) confirms how deeply he felt the crisis of naturalism.

The Gallery of the Academy of Fine Arts in Naples preserves these works by Antonio Mancini: "Head of a Girl" (1867, oil on canvas, 50x39 cm); "Study of Head from Behind" (1870, oil on cardboard, 31x43.5 cm, school essay); "Rosina" (1870, oil on canvas, 30.5x39.5 cm); "Profile of Woman in Black" (1871, 31.5x42.5 cm); "Lady in Red" (1926, oil on canvas, 191x101 cm, donated by the artist); "Clothing the Naked" (1871, charcoal, 105x158 cm, signed and dated).

Part of a room in the Ricci Oddi Modern Art Gallery in Piacenza is dedicated to him, featuring works such as "The Little Shepherd," "Woman with Inkwell," "Little Servant," "Portrait of the Father," "Woman at her Toilette," "Woman with Red Fan," and "Seated Musketeer."

Among the most important and prestigious collections of his works is that of the Museum of the Nineteenth Century (Museo dell'Ottocento) in Pescara, Abruzzo, where seventeen paintings are preserved, including "Truth" (1873) and "Little Priest in Prayer" (circa 1873).