In ancient times, the Collao plateau was inhabited by Aymara groups (Collas, Zapanas, Kallahuayos and Lupacas). The Quechuas came later.

According to chronicler Inca Garcilaso de la Vega, these ancient times coincide with the legend of Manco Capac and Mama Ocllo, who emerged from the waters of Lake Titicaca to found the Inca Empire.

The Aymara culture, also known as Putina, was the most important and influential pre-Hispanic culture in the region.

During the Viceroyship, Puno was the obliged route for travelers going to Potosí, Bolivia. In 1668, viceroy Conde de Lemos established San Juan Bautista de Puno as the capital of the province of Paucarcolla. Later, it was called San Carlos de Puno, in honor of the ruling king, Charles II of Spain.

In 1870, the railway route Arequipa-Puno was installed and navigation in Lake Titicaca started.

In 2007, a meteorite landed here, rupturing a natural deposit of arsenic, sickening the locals.