The earliest known inhabitants of the Mines of Spain State Recreation Area during historical times were the Mesquakie Indians. Their village was located just south of where the Julien Dubuque Monument now stands, at the mouth of Catfish Creek. From this site, the Indians carried on a fur trade with French voyagers. They also worked the lead mines for many decades dating back to before the Revolutionary War. There is evidence of prehistoric Indian cultures, some dating back as much as 8000 years. Mounds, village sites, rock shelters, trading post sites, and campsites dot the landscape.

Dubuque is credited as being the first European to settle on what is now Iowa soil in 1788. In 1796, Dubuque received a land grant from the Governor of Spain who resided in New Orleans at the time. The grant gave permission for Julien Dubuque to work the land which was owned by Spain, and specified the 189-square mile area to be names as "Mines of Spain". Dubuque eventually married Potosa, daughter of the Mesquakie Indian Chief, Peosta. Dubuque died March 24, 1810.

Lead mining was a major part of this area's history, first by the Indians, and in later years (late 1830s through the 1850s) by European miners and farmers. The Civil War caused renewed lead mining activity which waned after the war but continued until 1914.

The Julien Dubuque Monument, built in 1897, sits high above the Mississippi River and provides the "landmark" for the Mines of Spain Area. Julien Dubuque is buried on this site which provides a scenic vista of the 1380-acre Mines of Spain, the city of Dubuque, the Mississippi River Valley and of Illinois. When Dubuque died, the Mesquakie buried him with tribal honors beneath a log mausoleum at the site where the current monument now stands.