The shock result was delivered after nearly three hours of a big-serving contest in which Frenchman Henri boomed down 10 aces.
Lopez hit 13 of his own and won 72 per cent of his services points but the Spaniard could not get the better of 30-year-old qualifier Henri.
"I almost cannot believe it," said Mathieu. "I panicked a bit at the beginning of the match, he played very well.
"I'm moving better now and started playing better during the important points. I'm happy to win three matches in a row in three days during my first month back in competition."
Fifth seed Gasquet continued his decent form so far this season to post his sixth win in 2012, to three defeats.
Alexandr Dolgopolov, the sixth seeded Ukrainian, was beaten 6-7 (4) 6-4 6-2 by Lukasz Kubot of Poland to end his interest in the tournament early on, while 2005 and 2007 finalist Ivan Ljubicic of Croatia was bounced out 7-6 (6) 6-3 by Dutch wild card Jesse Huta Galung.
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