Blake, once ranked No. 4, played his 51st match at River Oaks Country Club where he is a crowd favorite but Monfils won cheers for his hustle playing his first match in the city.
Monfils, who played in only 10 tournaments last year because of a knee injury, matched the sixth-highest total of aces in the tournament. He will next face top-seeded Nicolas Almagro of Spain.
Monfils broke Blake in the 11th game of the second set on three straight errors by Blake and wrapped it up quickly with a love final game that included two aces. He won at the first match point on Blake's backhand error.
"I am 100 percent with the level the way I played," Monfils said. "I was happy the way I was moving. I can say it's a nightmare (injury) behind me so I am very happy."
Blake held after six break points in the eighth game of the first set but his serve failed him in the 10th game and the set eventually went to a tiebreaker. The score was tied at 3-3 in the tiebreaker when Monfils won three straight points and then capped the set with an overhead at set point.
"He really makes it tough out there," Blake said. "He makes you work hard to win points and combining that with a pretty big first serve. When that's going in, that makes a big difference."
Monfils applauded the crowd after his win but said he didn't hear their cheers during the match.
"It's been four weeks since I played so I was more focused on winning this match and hoping there was no more pain," Monfils said. "The crowd was very fair today. I knew it would be tough because James is a big favorite here."
Rhyne Williams of the United States, playing on a wild card, beat Guido Pella of Argentina 7-5, 7-5 in an earlier first-round match.