Del Potro, former US Open champion ranked 145 in the world after an injury-hit few years, stunned the Serb with a powerful display to win 7-6 (4), 7-6 (2) in the biggest upset in the tennis tournament.
Wimbledon Mega Monday: Roger Federer, and Andy Murray will begin the tournament in two separate matches while Russia's Maria Sharapova plays in the women's singles game.
Five former champions, including the reigning men's and women's title holders, will be in action at the U.S. Open on Tuesday, offering a tantalising look at the past, present and possible future of the Flushing Meadows honour roll.