Zandomeneghi, whose father and grandfather were sculptors, was born in Venice and enrolled in the Venice Academy in 1856. A supporter of Garibaldi, his political beliefs necessitated a move to Florence in 1860. There he met a number of the artists known as the Macchiaioli, including Telemaco Signorini, Giovanni Fattori and Giuseppe Abbati, and he joined them in painting landscapes outdoors. Painting outside of the studio, "en plein air", was at that time an innovative approach, allowing for a new vividness and spontaneity in the rendering of light.
In 1874 Zandomeneghi went to Paris, where he was to spend the rest of his life. He quickly made the acquaintance of the Impressionists, who had just had their first group exhibition. Zandomeneghi, whose style of painting was similar to theirs, would participate in four of their later exhibitions, in 1879, 1880, 1881, and 1886. Like his close friend Edgar Degas he was primarily a figure painter, although Zandomeneghi's work was more sentimental in character than Degas'. He also admired the work of Mary Cassatt and Pierre-Auguste Renoir, and his many paintings of women in their domestic routines follow their example. To supplement the meager returns from the sale of his paintings, Zandomeneghi found work drawing illustrations for fashion magazines.
He took up working in pastels in the early 1890s, and became especially adept in this medium. At about this same time his reputation and his fortunes were enhanced when the art dealer Durand-Ruel showed Zandomeneghi's work in the United States. From then on he enjoyed continuing modest success until his death in Paris in 1917.