David Ferrer (World No. 5)
At 30 years old, the veteran Spaniard is playing the best tennis of his life. Coming off of three consecutive Grand Slam quarterfinals appearances and a semifinals appearance at the World Tour Finals, Ferrer will be hoping to make the fourth Grand Slam semifinals of his career.
He was drawn into the quarter of the bracket where Rafael Nadal would have been, and that quarter is wide open. Ferrer should be the favorite to reach the semifinals, with American John Isner being his toughest competition along the way.
Ferrer is a respectable 5-8 lifetime against Novak Djokovic, who he will likely face in the semifinals if he gets that far.
Ferrer is far from being the favorite at the U.S. Open this year, but his chances are arguably the best of any man outside the Big Four (via Yahoo! Sports).
Juan Martin del Potro (World No. 8)
2009 U.S. Open champion Juan Martin del Potro is getting back into form after a rough 2011. He made back-to-back Grand Slam quarterfinals to start 2012 at the Australian Open and Roland Garros.
However, the U.S. Open is historically his best tournament.
John Isner (World No. 10)
With his classically American style, John Isner is a pure hard-court player. He serves hard, hits hard, and brings his A-game to hard-court tournaments. While he has never reached even the fourth round of a Major or Masters tournament on any other surface, he is a threat to even the Big Four on hard courts.
Even when he was straight out of college, Isner reached the third round of the 2007 U.S. Open—an impressive feat for someone who had never played against top talent before. Last year he reached his first Grand Slam quarterfinals at the 2011 U.S. Open.
Already this year, Isner has reached the finals of the Indian Wells hard court Masters 1000 and the semifinals of the Canada hard court Masters 1000. He was luckily drawn into the quarter of the U.S. Open bracket that would have contained Rafael Nadal. This makes him one of the favorites to reach the semifinals.
The biggest road block in his way will be world No. 5 David Ferrer.
Andy Roddick (World No. 21)
The name Andy Roddick does not draw the attention it did in 2003 when he took home the U.S. Open trophy. However, when he plays his best game, he is one of the best hard-court players in the world.
His ceiling is still at least as high as that of leading American John Isner.
Roddick—though inconsistent elsewhere—is always good in New York. Last year he reached his eighth U. S. Open quarterfinals, despite having one of his worst seasons. The path he will have to take this year is a difficult one. He will likely have to beat 2009 champion Juan Martin del Potro and 2011 champion Novak Djokovic in order to reach the finals.
However, if he can bring his top form to the Open this year, he stands a chance against anyone else there.