Scientists working on research for the National Oceanic and Atmospheric Administration predicted the hypoxic zone could cover as much as 6,213 square miles this year.
Such areas are marked by depleted oxygen levels in the water. It's predominately the result of excessive nutrient pollution from human activities, NOAA said.
Last year's hypoxic zone -- a so-called dead zone -- covered 6,765 square miles. The largest zone was more than 8,400 square miles in 2002.
"Regardless of the size of the dead zone, we should not lose sight of the ongoing need to reduce the flow of nutrients to the Mississippi River and thus the Gulf," NOAA Administrator Jane Lubchenco said in a statement.
NOAA says the dead zone has a direct effect on commercial and recreational fishing. Commercial fishing in the Gulf of Mexico generated $629 million in 2009.