Frenchman Simon had won four of his previous five meetings with the big-serving American and looked on course to record another victory early on in Nottingham.
But 12th-seeded Querrey fought back from losing the first set and, aided by 26 aces, he overcame the challenge of Simon 5-7 7-6 (10/8) 6-4 in just over two hours.
Querrey is now the only seed left standing after number four Leonardo Mayer was also sent crashing out at the quarter-final stage, beaten by Denis Istomin.
Argentinian Mayer had been pushed hard by Jiri Vesely in the last 16 before winning through 7-6 (7/2) 7-6 (7/5) but he could not repeat the feat in another hard-fought clash against Istomin.
Mayer actually fashioned a match point but Uzbekistan’s Istomin survived before going on to claim a 6-3 6-7 (8/10) 7-6 (8/6) triumph.
Istomin, who saved all seven break points as he held off Mayer, will next face Cypriot Marcos Baghdatis, who had a much easier time earlier on against Simone Bolelli, knocking out the Italian 6-4 6-4.
Baghdatis has yet to drop a set at Nottingham and beat top seed David Ferrer in the second round.