James H. Holmes was born in New York state in May 1833. Later living in Virginia, in the mid-1850s he went to territorial Kansas to undertake agricultural experiments in the new territory, after studying agricultural chemistry. He was also involved with the Clubbs Vegetarian settlement, located on the Neosho River.

Becoming involved with the free state cause, in Kansas Holmes became one of John Brown's cronies and was present at the Battle of Osawatomie. In April 1861 he joined James H. Lane's Frontier Guard in protecting President Abraham Lincoln and was later appointed territorial secretary for New Mexico under Lincoln.

Holmes married Julia Anna Archibald in Lawrence, Kansas in 1857, with whom he had several children. In 1858 the couple climbed to the top of Pikes Peak in Colorado; Julia Archibald Holmes was the first known Euro-American woman to make the ascension. After their divorce in 1870, he married Esther Maria Eavitt in 1878, and they had six children. He later married Grace Silveria in 1897 and died in November 1907.