Potaro-Siparuni is a region bordering the region of Cuyuni-Mazaruni to the north, the regions of Upper Demerara-Berbice and East Berbice-Corentyne to the east, the region of Upper Takutu-Upper Essequibo to the south and Brazil to the west. The main towns in the region are Kangaruma, Orinduik, Potaro Landing, Mahdia, Saveretik and Tumatumari.

The Potaro-Siparuni Region gets its name from the Potaro and Siparuni Rivers, which are tributaries of the Essequibo River.

Predominantly forested highland with a small portion of hilly sand and clay, this region is home to the famous Kaieteur and Orinduik Falls. The Kaieteur is one of the highest single-drop waterfalls in the world, and it is one of the beautiful sights in the Guyana. The waterfalls of this region are great tourist attractions.

There are few people in this region, and they are involved in gold and diamond mining and forestry. Mazda Mining Company Ltd has the largest operation in this region.

Many of these mining companies are destroying the rivers they work in especially the Essequibo and Konawaruk Rivers.

The Iwokrama Rainforest Project is partly located in this region. The project studies how the rainforest can be used in the country's development (for example, by providing timber) without being destroyed or depleted.