Tsonga, the 2008 Australian Open runner-up, lost 5-7, 6-4, 7-6 (10-8) to fellow Frenchman Arnaud Clement.
Clement was victorious after staving off a match point at 7-8 in the third-set tie-break.
"I was expecting a tough match for sure," Tsonga said. "I made a few errors that I am not used to making, but that's no excuse. He played well."
Simon won 85 percent of his service points, including six aces, in a 7-6 (7-5), 6-3 win over another Frenchman, fifth-seeded Julien Benneteau.
"I was struggling with my returns a bit in the first set (but) in the second set, I started to return much better and was able to control the points," Simon said.
Also winning were No. 3 Ivan Ljubicic of Croatia and France's Michael Llodra.