The No. 2 seed and Blake traded the final eight games of the set, leading to the decisive tiebreak. Del Potro took control from there and won when Blake was unable to return his serve.
Del Potro, the 2008 tournament champion, is still working his way back from wrist surgery last year that derailed his season. He is ranked 19th in the world after dropping as low as No. 484 in February.
"I think I'm still a little far from the top-10 players," Del Potro said. "It's a long road to get there. I was playing really well before I got here."
Yen-Hsun Lu of Taiwan had the day's biggest upset, defeating No. 3 seed Marcos Baghdatis of Cyprus 6-3, 6-4 to set up a matchup against Harrison, who is attempting to make consecutive semifinals appearances.
Harrison is coming off a strong showing in Atlanta, where he won three matches before falling to Mardy Fish. The 19-year-old's win over Russell was his third in four career tries.
Fish, the tournament's No. 1 seed, will play his first match on Thursday against Gilles Muller following a bye.
Ernests Gulbis of Latvia had little trouble in defeating qualifier Daniel Kosakowski 6-2, 6-4 in their second-round match. Gulbis will play del Potro in the quarters.
Harrison moved into the world's top 100 for the first time with his finish last week. His continual rise has some observers thinking he could assume the title as the next great American player.
"It's a privilege to be talked about like that. I've put myself in a position where people are even mentioning my name in the same sentence as Andre Agassi and Pete Sampras," Harrison said. "I haven't accomplished anything near what they have in their careers, so I have a long way to go. But I do believe in myself, I do believe that I have the ability to do it."
Harrison, who grew up idolizing Sampras, isn't fazed by comparisons of his game to that of former greats.
"It's more something that is going to motivate me to go out and get better results," he said.
Baghdatis, ranked 30th in the world, was playing his first match of the tournament after receiving an opening-round bye. He was facing Lu for the second time.
Their first affair in 2009 lasted a grueling two hours, 49 minutes, with Baghdatis needing three sets for the victory.
"It really helps that it was the same guy from two years ago," said Lu, a quarterfinalist at last year's Wimbledon. "It gave me a little bit of confidence."
Gulbis rode the momentum from Tuesday's upset of fifth-seed Xavier Malisse against the inexperienced Kosakowski, playing in his first year as a professional.
This is Gulbis' third tournament under the tutelage of coach Guillermo Canas. The two began working together at Wimbledon and the relationship appears to be paying dividends.
"On the court I didn't really have someone to push me," Gulbis said. "We were working hard, spending a lot of hours on court. And then everything just starts to come back. It's all basically about practice and confidence. That's all there really is to it."