The announcement by the Obama administration follows a 2,000 percent increase in uranium mining claims in the area in the past seven years, the Los Angeles Times reported.
The move is designed to protect the critical Colorado River watershed from possible contamination.
It will also prevent the Grand Canyon panorama from being gradually industrialized.
Interior Secretary Ken Salazar said the ban extends a two-year moratorium that was set to expire July 20, McClatchy Newspapers reported.
"What drives us first is protecting the arteries of lifeblood, of water" in the area, Salazar said.
The mining industry and its congressional supporters warned removing such a vast swath of land from industrial development risks jobs and economic growth.
A spokeswoman for the National Mining Association called the government's decision "scientifically unsupportable" and said it "sets a troublesome precedent."