The big-serving Soderling, who won at Lyon in 2004, lost his previous three finals this season.
Third-seeded Jo-Wilfried Tsonga played Julien Benneteau in an all-French match later Saturday.
Soderling, who clinched the victory with a smash at the net, goes for his third career title.
Soderling led 5-4 and had Simon trailing 15-30 on his serve but then crumbled to lose the first set.
The players swapped breaks at the start of the second set. At 2-1 up, Soderling called for a trainer to treat blisters on his left foot. He broke the Frenchman again to lead 3-1 and then saved two break points with aces.
Simon waited until the eighth game of the third set before getting a chance to break back, but his shot hit the net.
Simon, who has three titles this year and reached the Madrid Masters final, has climbed into the top eight of the Champions Race this week, which determines qualifiers for the Masters Cup.
The final spots will be decided next week at the Paris Masters.
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Soderling to face Benneteau in Lyon final
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