The former mining camps (now ghost towns) of Harshaw, Duquesne and Lochiel lie to the southeast along the eastern margin of the Patagonia Mountains.

[6] According to the United States Census Bureau, the town has a total area of 1.3 square miles (3.3 km2), all land.

The area where Patagonia is located provided Native-American communities, with plentiful hunting and fishing opportunities.

Archaeologists have identified the remains of Native American settlements, resource processing sites, and petroglyphs in the area surrounding Patagonia.

[7][8][9][10] In 1539, Spanish explorer Fray Marcos de Niza entered the area near Lochiel on the Mexican border.

[12] The main Native American tribes in the area at that time were the Sobaipuri and Papago (Tohono O'odham).

[7][8][9][10] According to Gilbert Quiroga, president of the Patagonia Museum, Welsh miners came to this region from Patagonia, a region encompassing the vast southernmost tip of South America, shared by Argentina and Chile, divided by the Andes mountains.

Americans of European descent from the East Coast of the United States began to arrive in the area.

In 1867, the United States Army established a military post called Camp Crittenden close to Sonoita.

The camp, which later was renamed Fort Crittenden, was involved in a campaign against the Apache with the intention of protecting the American pioneers in the area.

They petitioned the United States Post Master General to name the town Patagonia after the nearby mountain.

Patagonia was recognized as the official name of the town in 1900 by the United States Postal Office Department in Washington, D.C.[7][8][9][10] That same year, a two-story railroad depot was built and Patagonia became the commercial center of the mining district in the Santa Cruz County.

The arrival of the New Mexico and Arizona Railroad to Patagonia gave the ranchers and miners a new outlet for their products and access to manufactured goods.

[19][7][8][9][10] By 1917, Patagonia had running water, an Opera House, three hotels, a schoolhouse, two parks and several stores and saloons.