The city of San Carlos de Río Negro was founded in 1759 as a camp set up by the expedition captained by José Solano y Bote.

José Solano y Bote set up his exploration base there on the banks of the Rio Negro with the few men that had survived the trek up the Orinoco River.

Most of the men that accompanied the expedition, including the famous Swedish botanist Pehr Löfling, succumbed to tropical diseases, especially yellow fever.

In May 1800, the explorers Alexander von Humboldt and Aimé Bonpland visited the town, constituting the southernmost point of their expedition of the Amazon basin.

The city is located a few kilometers from the mouth of the Casiquiare canal, an important fluvial artery that connects the Amazon Basin with the Orinoco River, thus uniting Venezuela, Colombia and Brazil, and is 65 metres (213 ft) above sea level.