In 1498, Bartolome Colon had a fort built on the Ozama River delta, which would later become the first permanent European settlement in the New World (Santo Domingo).

The estuary at that time, "teemed with fish and where the Indians raised cassava and yams," according to Floyd.

At the end of the journey it bisects the capital, Santo Domingo, into eastern and western halves.

The river has several tributaries, with a combined area of 2,706 square kilometers (1,045 sq mi).

[4] In August 2020, The Ocean Cleanup organization deployed an Interceptor Original, one of their solar-powered, automated systems, to help combat the flow of plastics and trash into the Caribbean Sea.