Isner, the No. 1 seed who reached the finals of this event in 2010 and 2011, outlasted Blake 7-6 (7-1), 7-6 (7-5) and will face former world No. 1 Lleyton Hewitt in the semifinals.
Hewitt rallied past No. 3 seed Ivan Dodig 1-6, 6-3, 6-0.
In Saturday's other semifinal, second-seeded Kevin Anderson will take on Ryan Harrison.
18-year-old elf alleges mall Santa pinched her buttocks on the job
Theater accidentally screens 'Nymphomaniac' trailer instead of Disney's 'Frozen'