Scientists said the zone could spread to around 8,717 square miles, which is just short of the 2017 record but far larger than the five-year average of 5,770 square miles.
The impending disaster has been blamed on unusually high rainfall across the US Midwest in spring that has washed vast amounts of farm fertilisers along streams and rivers through the Mississippi River Basin out into the Gulf.
The nutrients in the fertilisers feed algae that die, decompose and deplete the water of oxygen, scientists at Louisiana State University said.
"When the oxygen is below two parts per million, any shrimp, crabs, and fish that can swim away, will swim away," ocean ecologist Nancy Rabalais told National Geographic magazine.
"The animals in the sediment [that can't swim away] can be close to annihilated."
The problem might get even worse if any more significant tropical storms wash out more farm-fed nutrients, the scientists said.
Sewage run off, caused by the spring floods, also adds to the problem.
Scientists with the National Oceanic and Atmospheric Administration (NOAA) predicted a slightly smaller 7,829 square mile spread. The record was 8,776 square miles set in 2017.
"A major factor contributing to the large dead zone this year is the abnormally high amount of spring rainfall in many parts of the Mississippi River watershed," the agency said in its annual "dead zone" forecast.
A solution would be to keep fertiliser and sewage run-off from getting into the rivers, NOAA said.
A Mississippi River/Gulf of Mexico Watershed Nutrient Task Force has been monitoring the problem and has set goals to reduce run-off.
It comes after scientists last year stumbled on an even bigger dead zone in the Gulf of Oman, as well as a 2015 discovery of swathes of oxygen-deprived water up to 100 miles long swirling in the Atlantic Ocean.
Additional reporting by Reuters
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