Roddick, the tournament's fifth seed and ranked 21st, overcame a shaky start to beat Blake 7-6 (8-6), 7-6 (8-6) in the final hard-court tournament before the U.S. Open.
In other second-round matches played Monday, Belgium's David Goffin upset 10th-seeded Viktor Troicki of Serbia 3-6, 6-4, 7-5, while the match between seventh-seeded Sam Querrey and Colombia's Santiago Giraldo was suspended by rain.
It will be resumed Tuesday, with Querrey having won the first set 6-3.
"I've rarely been unhappy walking off the court with any win," said Roddick, a former world No. 1 and U.S. Open champion who has battled injuries the past two years.
"I was fortunate to get through the first set, because (Blake) came out of the gates pretty hot. The second set I played well. I've been lucky a lot in my career. I'm good at winning those type of matches where it doesn't look that great all the time."
Roddick had 11 aces, but had to overcome an early break to force a tiebreaker in the first set. He then got a break in the second set to force another tiebreaker and improve to 9-3 against Blake.
"There were a lot of points that could've turned things around," Blake said. "It's getting to be a broken record. I'm losing a couple matches where I'm playing well, but not playing the big points as well as I need to. ... Right now, I'm pretty frustrated with it."
In first-round matches, Lukasz Kubot of Poland defeated Spain's Tommy Robredo 6-1, 2-6, 6-2; Michael McClure downed Columbia's Alejandro Falla 6-1, 6-4; Germany's Benjamin Becker beat Japan's Tatsuma Ito 6-3, 4-6, 6-2; Sergiy Stakhovsky of the Ukraine downed Gilles Muller of Luxembourg 7-6 (7-1), 6-4.
Also, Ernests Gulbis of Latvia beat Argentina's Carlos Berlocq 6-4, 7-5; Robin Haase of The Netherlands defeated Russia's Nikolay Davydenko 6-2, 6-3; Donald Young downed Argentina's Leonardo Mayer 4-6, 6-3, 6-2; Slovakia's Martin Klizan beat France's Benoit Paire; Taiwan's Yen-Hsun Lu downed Slovakia's Lukas Lacko 6-3, 7-6 (7-3); and Brazil's Thomaz Bellucci advanced when Cyprus' Marcos Baghdatis withdrew in the second set because of an injury.
Roddick, Querrey and Troicki were the only top seeds in action Monday, with the rest opening play Tuesday.
Among them will be third-seeded John Isner, the tournament's defending champion; top-seeded Jo-Wilfried Tsonga of France, No. 2 seed Tomas Berdych of the Czech Republic and fourth-seeded Alexandr Dolgopolov of the Ukraine.