Escitalopram, a selective serotonin reuptake inhibitor (SSRI), may induce seizures, particularly in epileptic patients. In this study, we investigated the effect of escitalopram in Na_v1.2 voltage-gated sodium channels (VGSCs) transfected HEK293 cells. Na_v1.2 VGSCs current decreased by approximately 50.7±8.3% under treatment with 100 µM escitalopram. The IC₅₀ of escitalopram against Na_v1.2 VGSCs was 114.17 µM. Moreover, the treatment with 100 µM escitalopram changed the voltage-dependence of inactivation and the voltage at half-maximal inactivation shifted significantly from −50.3±3.7 to −56.7±6.0 mV toward negative potential under treatment with 100 µM escitalopram. Surprisingly, the treatment with 100 µM escitalopram also changed the voltage-dependence of activation and the voltage at half-maximal activation shifted significantly from −13.8±4.6 to −21.5±3.9 mV toward negative potential under treatment with 100 µM escitalopram. These findings suggested that escitalopram might be able to inhibit Na_v1.2 VGSCs current and affects both activation and inactivation states of Na_v1.2 VGSCs.