Frenchman Simon had no answer to the Colombian, who saved all five break points he faced and broke six times himself on his way to sealing victory in just 66 minutes.
Third seed Nicolas Almagro eased into the second round with a 6-2 6-3 win over fellow Spaniard Pablo Andujar while fifth seed Jerzy Janowicz was forced to battle his way through, the Pole edging up-and-coming Spaniard Pablo Carreno Busta 7-5 7-6(7).
Almagro, in a rich vein of form following a successful Asian swing, needed just an hour and five minutes for victory, while Janowicz fired down 14 aces in a strong service display as he claimed his 25th win of the season.
Valencia Open results
3-Nicolas Almagro (Spain) beat Pablo Andujar (Spain) 6-2 6-3
5-Jerzy Janowicz (Poland) beat Pablo Carreno (Spain) 7-5 7-6(7)
Alejandro Falla (Colombia) beat 6-Gilles Simon (France) 6-1 6-0
Michal Przysiezny (Poland) beat Fernando Verdasco (Spain) 6-3 7-6(1)
Mikhail Youzhny (Russia) beat Bernard Tomic (Australia) 3-6 6-4 4-1 (Tomic retired)
Julien Benneteau (France) beat Feliciano Lopez (Spain) 6-3 6-1
Joao Sousa (Portugal) beat Guillermo Garcia-Lopez (Spain) 6-3 7-5