Blake won nearly three-quarters of the points when serving and didn't allow del Potro a break-point opportunity in a 6-4, 6-4 victory.
Blake won 20-of-24 points on serve in the second set and closed the match with his second break of the day in moving to the tournament quarterfinals.
No. 5-seeded Kevin Anderson defeated Tommy Haas 6-7 (3-7), 6-4, 6-4. There were only two break-point chances in the match -- one in each the second and third sets and Anderson converted both.
Milos Raonic, the sixth seed, also won a spot in the quarterfinals, taking out Philipp Petzschner 6-3, 6-3. He lost 10 points in nine service games.
The first round was completed with Bernard Tomic getting by Jurgen Zopp 7-6 (7-5), 4-6, 6-0; Grigor Dimitrov sweeping past Ryan Sweeting 6-3, 6-1; and Sebastian Rieschick topping Michael Ryderstedt 6-4, 3-6, 6-3.
Tomic's victory earns him a second-round match against No. 1-seeded Gael Monfils.