Seventh seed Sock won the only break point he managed off his countryman to claim the first set, then captured the tie-breaker to oust the 2011 and 2012 Hall of Fame winner in 88 minutes.
That sends 21-year-old Sock into a Saturday semi-final against 33-year-old Australian third seed Lleyton Hewitt, who ousted US sixth seed Steve Johnson 6-4, 6-4 in the day's other quarter-final at the $474,000 grass-court event.
Hewitt, who won his first ATP title since 2010 at Brisbane in January, seeks his third consecutive trip to the championship match. He lost to Frenchman Nicolas Mahut in last year's final and to Isner in the 2012 title match.
Saturday's other semi-final will send Croatian second seed Ivo Karlovic against Australian Samuel Groth, who upset Mahut in the quarter-finals.