Alexander began with Harper's Weekly in 1875, but he left this position two years later to study at the Royal Academy in Munich. After a few months there he became one of the "Duveneck Boys," a group of American students (among them his old friend Beatty) who worked with the expatriate painter Frank Duveneck at Polling, Bavaria. Alexander traveled with the Duveneck group to Italy, where he first met Whistler and James, then set up a studio in New York in 1881 and resumed his career as an illustrator. Though he undertook a variety of assignments, including views of New Orleans for Harper's Weekly in 1881 and Irish landscapes and genre scenes for The Century in 1886, his strong suit, in which he had already made great strides as a painter, was portraiture. His portraits, published in The Century between 1886 and 1893, were primarily of literary men such as Robert Louis Stevenson, Thomas Hardy, John Burroughs, and the historian George Bancroft. John Beatty, in his introductory essay for the catalogue of the 1916 memorial exhibition, praised these drawings as "masterpieces of simple and direct delineation of character."

John White Alexander was best known in both his day and ours for his elegant, evocative portraits of women, achieved international prominence in the 1890s. During his residence in Paris from 1891 to 1901 he was ranked with Edwin Austin Abbey, John Singer Sargent, and James McNeill Whistler as a leading American expatriate painter. His circle of friends included such eminent artistic and literary figures as Whistler, August Rodin, Stéphane Mallarmé, Octave Mirbeau, Oscar Wilde, and Henry James. Following his return to New York, he enjoyed great success as a fashionable portraitist and served as president of the National Academy of Design from 1909 until his death.

Alexander was also closely associated with Carnegie Institute. He had grown up in Allegheny City, now part of Pittsburgh, and since childhood had been a close friend of the Institute's first director of fine arts, John W. Beatty. In 1897 he presided over the Carnegie International's Paris advisory committee and several years later executed a major mural project for the Institute, an allegory of Andrew Carnegie's philosophy of industry and democracy entitled Apotheosis of Pittsburgh (1905-15).

In 1905 John White Alexander was commissioned to decorate the main stairway of the newly expanded Carnegie Institute with sixty-nine panels that would cover more than five thousand square feet. It was the largest mural commission ever given to an American artist, for which Alexander was paid $175,000, the largest sum any artist had ever received for a single project.

Like Andrew Carnegie, Alexander had worked his way up from office boy to world-renowned celebrity. During his childhood in Pittsburgh, he taught himself to draw by copying illustrations in magazines, and in 1875, he left for New York determined to become an illustrator for Harper's Weekly. At first he could get work only as an office boy, though success as an illustrator came quickly. Alexander, however, soon determined to achieve equal prominence as a painter, and to that end studied painting at the Royal Academy in Munich in the late 1870s. His mature style did not develop until about 1890, when he moved to Paris and established contact with members of the Symbolist movement. Soon Alexander became the foremost American practitioner of Art Nouveau, composing his paintings in a sinuous, flowing, decorative manner, with asymmetrical compositions and delicate pastel colors. After his return to the United States in 1901, Alexander was showered with commissions and honors, including the presidency of the National Academy of Design; but perhaps the most notable was the Carnegie Institute commission.

Alexander's subject for The Crowning of Labor echoed the writings of Andrew Carnegie, which described how the higher levels of human culture are built up from the toil of manual laborers, and they became the first American murals to realistically depict the processes of modern industry and to attempt to relate directly to the local community.

On the ground floor of the building Alexander depicted laborers in the mills of Pittsburgh, and on the second floor he continued his representations of men at work, with views of more laborers, smokestacks, blast furnaces, trains, and boats. In addition, he included scenes of steel girders being set into place in a distinctively modern form of building, the skyscraper. Above these emblems of human toil he placed floating groups of allegorical figures symbolizing labor and the higher achievements, such as art and science, made possible by hard work. In a series of twelve more panels leading up to the third floor, Alexander represented over four hundred figures in a tableau described by his wife as "the ceaseless, resistless, onward movement of the people."

When he died, Alexander had not yet completed the final group of panels on the third floor. A sketchbook survives with drawings of several allegorical figures, including Painting, Music, Chemistry, and Astronomy, but because Alexander worked without finished preliminary drawings, it is not possible to reconstruct his exact intentions. Carnegie Institute honored Beatty's friend the year after his death with a traveling memorial exhibition of his work.