Seppi, of Italy, withdrew during the first set due to an injured right foot, allowing Del Potro to grab a 4-1 victory on the hardcourts at the Lindner Family Tennis Center.
The Argentine earned a second-round date with Roger Federer. Del Potro ousted Federer in the 2009 U.S. Open final.
Blake dropped the first two games in the third set before rallying to take the next six for the win.
The top seeds here are also the top players in the world -- Novak Djokovic, Rafael Nadal, Federer and Andy Murray. Federer titled here for a fourth time by edging out American Mardy Fish in last year's final. Djokovic was the runner-up here in 2008 and 2009. Murray beat Djokovic in the '08 Cincy final.
Nine of the last 10 champions here have held the No. 1 ranking during their careers.
This is the final Masters event before the U.S. Open, which will commence August 29 in New York.
This week's winner will collect $496,000.