Top-seed Andy Roddick took care of his serve in the first set, then ousted defending tournament champion Steve Darcis of Belgium, 7-6 (1), 6-2, in the day's last match.
"Steve was making good shots early in the match, but I was trying to keep pressure on him, force him to keep making shots - and when he got into a (service) break situation he started to not make them,'' Roddick said.
"The last couple of years I've inched probably the wrong way (in terms of conditioning) and I'm getting back to where I need to be. I've played well so far this year, but don't have a win to show for it yet.''
Though Darcis took Roddick to a tiebreaker in the first set, Roddick gave up just five points on his service in the set, and had nine of his 20 aces, including the point that clinched the tiebreaker.
Roddick, who won this event in 2002, opened the second set with a service break and rode it from there, losing just two more service points.
Earlier, the top-seeded Caroline Wozniacki of Denmark rolled into the quarterfinals of the women's draw with a 6-1, 7-6 (1) victory over Severine Bremond of France.
Hewitt, a former world No. 1 player who underwent major hip surgery last August and has slipped to No. 109 in the world, was down a set and struggling with his first serve for most of the night.
He survived five break points to hold serve in the first game of the second set when Blake sent a backhand wide.
"I think he lost a bit of confidence there, and after surviving I started to get more into points, and James got a bit tentative,'' said Hewitt, who won 15 of the next 20 points and broke Blake twice for a 4-0 lead in the second set.
Both players held serve in the third set until 3-3, when Hewitt broke Blake after a couple of mishits.
"He took advantage of his opportunities, and I didn't,'' said Blake, playing on an ankle he injured during a tournament last week in San Jose. "The ankle was fine. I just didn't stay consistent.''
Serving for the match, Hewitt survived three break points, got the advantage on a serve Blake couldn't handle, then won with his seventh ace of the night, and sixth of the third set.
"I served well, and played well when I had to,'' said Hewitt, who hadn't defeated a top 25 player in a year - but has won eight of nine matches against Blake.
In the other matches, In other men's matches,fifth-seeded Radek Stepanek of the Czech Republic defeated Kevin Kim of the United States 6-4, 6-2, American No. 7 Mardy Fish scored a 6-1, 7-5 victory over Lu Yen-hsun of Taiwan and eighth-seeded Sam Querrey of the United States earned a 7-6 (4) 6-4 win over Germany's Tommy Haas, who won here in 1999.
Philipp Petzschner of Germany defeated Finland's Jarkko Nieminen, 6-3, 6-4, while Robby Ginepri of the United States defeated Simon Greul of Germany 6-4, 6-4 for a possible chance at Roddick.
Wozniacki, 18, is looking to reverse a pattern after being eliminated by the eventual Memphis champion three straight years - Sofia Arvidsson of Sweden in 2006, and Americans Venus Williams in 2007 and Lindsey Davenport last year. She has yet to get past the quarterfinals in this event.
But in a breakout 2008 season, Wozniacki won three tournaments and vaulted from 68th to 12th in the world rankings. A win here could push her to 11th when new rankings come out on Monday.
"I'd like to be in the Top 10. I'd like to be No. 1,'' she said, "but I'm still working, trying to take each match as it comes, and trying to get better all around. I've still got lots of things I can improve.''
Third-seed Lucie Safarova of the Czech Republic survived a first-set tiebreaker and eliminated Vania King of the United States 7-6 (1), 6-3 to reach the quarterfinals.
In other second-round play, fourth-seeded Anne Keothavong of Great Britain also went through a tiebreaker before defeating Michelle Larcher de Brito of Portugal 7-6 (2), 6-4. No. 6 Sabine Lisicki of Germany defeated France's Stephanie Foretz 6-1, 6-4, and eighth seed Pauline Parmentier of France defeated qualifier Chanelle Scheepers 6-4, 6-1.
Hewitt upsets Blake; Roddick rolls on
Mauricio Pochettino Angry At Two Points Dropped
Hewitt upsets Blake; Roddick rolls on
