John Wesley Powell made note of the range on his 1869 voyage, and called them the Unknown Mountains. When he returned in 1871, he named them the Henry Mountains after Joseph Henry, a close friend who was secretary of the Smithsonian Institution. In 1875 Powell assigned a noted geologist, Grove Karl Gilbert, to study the unique volcanic features of the Henrys, a task which took Gilbert two separate field seasons in 1875 and 1876 to complete. Out of this study came one of the classics of modern geology, the Report on the Geology of the Henry Mountains, published by the U.S. Geological Survey in 1877. In this work Gilbert first identified the Henrys as a laccolithic range, formed by igneous intrusions into the surrounding sedimentary rocks. Gilbert's Report remains a standard work of geology; as Charles B. Hunt, a geologist who studied the Henrys in the 1950s, noted, "The Henry Mountains have been referred to in the geological literature of every language and are one of the localities most widely known to the science. No geologist needs to be introduced to them."

The rigors of the land have precluded any large-scale settlement of the Henrys or the surrounding regions. Evidence of prehistoric inhabitation by both the Fremont and Anasazi cultures is found in the surrounding area, but there is little or no indication of habitation in the mountains themselves. Nor did the Spaniards make any inroads into this isolated area. Although there have never been any permanent settlements in the Henrys themselves, the surrounding region was settled by Mormon pioneers as early as 1882, when Elijah Cutler Behunin moved his family to the present site of Caineville.