In 1871 at the age of twenty-two, Chase moved to Saint Louis, where he created still life paintings and attracted the attention of local patrons, who, in the fall of 1872, offered to send him abroad to work on his art. At the Royal Academy of Fine Arts in Munich, where he received his most decisive training, Chase was one of the many Americans, including Frank Duveneck, who studied there. After an extended visit to Venice with Duveneck in 1878, Chase returned to New York, where he began teaching at the Art Students League. He devoted much of his time and energy to teaching, not only at the League, but also the Brooklyn Art Association, the Pennsylvania Academy of the Fine Arts, the Shinnecock Summer School of Art, and the New York School of Art the last two of which he founded and was the most celebrated teacher of his time.

In 1875 he exhibited at the National Academy of Design in New York, and received a medal at the 1876 Centennial Exposition in Philadelphia. In 1878 Chase returned to New York to teach at the Arts Students League and he also gave private lessons in his studio. As a leader of the insurgent younger painters who challenged the authority of the National Academy of Design, he was a founding member of the Society of American Artists and, in 1880, was elected its president.

In 1881 he returned to Europe where he met the Belgian painter Alfred Stevens and came in contact with the work of the Impressionists. Their influence on Chase’s work was almost immediate and he soon began lightening his palette, as did so many others who were struck by the Impressionists at the time.

In 1884 Chase was invited to contribute to a group exhibition at the Palais des Beaux-Arts in Brussels alongside fellow American painters Whistler and John Singer Sargent. After meeting with Whistler in Brussels, Chase met up with him again the following year in 1885 in London and they both agreed to paint each other's portrait. Whistler did not live up to the agreement however and only Chase's portrait of Whistler was completed in that same year. (It now hangs at the Metropolitan Museum of Art in New York). Whistler was not happy with the Chase’s depiction and later described it as a 'monstrous lampoon'. Although not the best of friends, Whistler had a profound influence on Chase’s work especially in his full-length female portraits of the late 1880’s and early 1890’s.

In 1886 he married Alice Gerson, who was frequently his model, as were their many children. Chase painted a wide range of subjects, including figures, landscapes and cityscapes, studio interiors, still lifes, and, increasingly later in life, portraits, and he worked with equal brilliance in oil and pastel.

In 1891 he founded the Shinnecock Summer School of Art on Long Island where he taught until 1902. He also taught at the Brooklyn Art Association in 1887 and from 1891 to 1895, at the Chase School of Art, from 1897 to 1907 and at the Pennsylvania Academy of Art from 1896 to 1909. He encouraged his students to work directly from nature and advocated that they paint directly on to the canvas forgoing any initial preparatory sketch. His students included Charles Demuth, Georgia O'Keeffe, Charles Sheeler and Joseph Stella. Chase died in New York City in 1916.