It rises in the Guiana Highlands of Venezuela, where it descends northward to El Dorado, and turns eastward to meander through the tropical rain forests of the Cuyuni-Mazaruni Region of Guyana.

On January 2, 1895, the "Incident of the Cuyuni river", so named by the general Domingo Antonio Sifontes [es], was an armed confrontation between Venezuelans and British in the region of the river over the territorial dispute between Venezuela and British Guyana, which under Sifontes the Venezuelans left winners.

At dawn, British policemen led by an Inspector Barnes of England took an unoccupied military station of Venezuelan nationality, located on the left bank of the river.

The result was the withdrawal of the British and the capture of Barnes and his men, who were taken to the General Police Station, which increased tensions between the two countries amid an internal crisis in Venezuela.

[14] The town of Bartica is close to the mouth of the Cuyuni where it meets with the confluence of Essequibo and Mazaruni rivers.