In a letter to U.S. Interior Secretary Ken Salazar, the Florida Democrat called for a "massive python kill," The Wall Street Journal reported.
"We need to get a grip on pythons invading America's Everglades," Nelson said. "They are threatening endangered wildlife there -- and, Lord forbid, a visitor in the Everglades ever encounters one."
Burmese pythons, one of the world's largest snakes, can grow to be more than 20 feet long. The population in the Everglades, which may number 100,000, are believed to be descended from imported pets released when they became too large for their owners.
Gov. Charlie Crist is expected to sign a directive Wednesday allowing Burmese pythons to be trapped and killed on state land, The Miami Herald reported.
Nelson called for a ban on importing pythons last week after a Florida girl was killed by a pet snake that escaped from a terrarium.
Dan McLaughlin, a Nelson spokesman, told the Journal a summer hunt would be impractical because the snakes hide in saw grass.