Born near Cadiz, Ohio, he was a survey-field artist, primarily self taught, who earned a reputation as a skilled panoramic landscape painter of the Grand Canyon. He also did delicate watercolors in traditional style.

He was educated in the public schools of Georgetown, Ohio, and was a teacher until 1872. He then moved to Washington D.C. where he studied art with Theodore Kaufmann and did sketching of specimens for the Smithsonian Institution.

In 1872, succeeding Thomas Moran, he became field artist for the United States Geological Survey, called the Hayden Expedition, of what became Yellowstone Park. The leader was Ferdinand Hayden and from him, Holmes learned about much about geology. Holmes was with Hayden in 1874 on a Colorado survey, and in 1875, led the survey party in Arizona and New Mexico. By 1876, he was a full-fledged geologist.

In 1879, he went to Europe, and the next year he accompanied Clarence Dutton on a Grand Canyon geological exploration, doing "double page" panoramas, nine of them, that led viewers breathlessly to the Canyon edge. It was said that these views were the highest point ever reached in topographical illustration.

In 1884 to 1886, he did a study of Pueblo Indians in Mexico, and from that time, held positions as Head Curator of Chicago's Field Museum and Chief of the Bureau of American Ethnology from 1902 to 1920, when he became director of the National Gallery of Art.

He was a member of the Washington Watercolor Club and the Society of Washington Artists and has a watercolor in the collection of the National Portrait Gallery in Washington D.C.