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.
LGBT community has 'bullied the American people': Bachmann
Handler slams Piers Morgan: 'You're a terrible interviewer'