The bus accident occurred early on Monday on the outskirts of Guatemala City. In the initial search and rescue operation, personnel found 51 fatalities, which were taken to a hastily arranged morgue.
Ten injured people have been rescued from the bus, which is believed to have had around 70 people on board.
"This is a difficult day for the nation of Guatemala", said the president of the Central American republic, Bernardo Arévalo.
The fire chief, Carlos Hernandez, reports that the driver is believed to have lost control of the 30-year-old bus. The vehicle crashed into several smaller cars "before plummeting 20 meters into the polluted river".
The bus came from San Agustin Acasaguastlán, about nine miles from the capital, and authorities fear that many more passengers than allowed were on board.
Traffic accidents are a recurring problem in Central and South America, but Monday's bus crash is one of the worst. Over 50 people died in Peru in 2018 when a bus crashed onto a beach. 54 people were killed in Brazil in 2015 in a crash involving a tourist bus.
