It was originally a natural river inhabited at its mouth by the Tequesta Native Americans, but it was dredged and is now polluted throughout its route through Miami-Dade County.

Although it is widely believed that the name is derived from a Native American word that means "sweet water," the earliest mention of the name comes from Hernando de Escalante Fontaneda, a captive of Native Americans in southern Florida for 17 years, when he referred to what is now Lake Okeechobee as the "Lake of Mayaimi, which is called Mayaimi because it is very large".

[2] Reports on a Spanish Mission to the Biscayne Bay area in 1743 mention "Maymies" or "Maimíes" living nearby.

[4] In its original natural state, the river started at rapids formed by water from the Everglades flowing over a rocky ledge four miles (6.4 km) from its mouth.

Frederick H. Gerdes of the United States Coast Survey reported in 1849 that "[f]rom the upper falls to near its entrance into Key Biscayne Bay… water in the Glades was 6 feet 2.5 inches (1.892 m) above low tide.

The United States Army attempted to dig a channel through the sandbar at the mouth of the river in 1856, but stopped when it was decided that Fort Dallas would not be made permanent.

By the 1940s, dams were being installed on the canals leading into the Miami River to prevent salt water from traveling inland.

[12] At a site next to the river, archeologists in 2023 discovered numerous artifacts, "dating back to the dawn of human civilization 7,000 years ago.

[16] Because of continuing efforts by the United States Coast Guard, U.S. Customs and Border Protection (CBP), DEA and other agencies, the illicit trade has been minimized in recent years.

[22][23] Invoking the authority of Port State Control, the U.S. Coast Guard strongly enforces the numerous international and national regulations regarding safety equipment, construction, maintenance and manning of ships entering all U.S. ports, including the Miami River, and virtually eliminating the many dangerously substandard vessels that had sailed from the U.S. in previous years.

The group works closely with local law enforcement agencies, the U.S. Coast Guard, ICE, and others to maintain clear channels of communication and cooperation.

[26] Many of the ships sailing from the Miami River carry cargo to ports in Haiti including Port-au-Prince, Miragoâne, Cap-Haïtien, Port-de-Paix, Saint-Marc, Gonaïves, and Jacmel.

When the International Ship and Port Security Code and the U.S. Maritime Transportation Act of 2002 came into force (and in the prior runup) on July 1, 2004, most opportunities for crime were eliminated.

The "lower end" of the river has been the subject of much renovation and building of high rise offices, hotels, and living structures.