Propylparaben, a commonly used antimicrobial preservative, has been reported as an anticonvulsant agent targeting neuronal Na⁺ channels (Na_V). However, the specific features of the Na_V channel inhibition by this agent have so far not been extensively studied. Moreover, it is still unclear if it shares this pharmacological activity with other parabens. Here, we fully characterized the mechanism of action of the inhibitory effect that propylparaben and benzylparaben induce on human Na_V 1.2 channel isoform (hNa_V1.2). We established a first approach to know the parabens structural determinants for this channel inhibition. The parabens effects on hNa_V1.2 channel mediated currents were recorded using the patch-clamp whole-cell configuration on hNa_V1.2 stably transfected HEK293 cells. Propylparaben induced a typical state-dependent inhibition on hNa_V1.2 channel carried current, characterized by a left-shift in the steady-state inactivation curve, a prolongation in the time needed for recovery from fast inactivation and a frequency-dependent blocking behavior. The state-dependent inhibition is increased for butylparaben and benzylparaben and diminished for methylparaben, ethylparaben and p-hydroxybenzoic acid (the major metabolite of parabens hydrolysis). Particularly, butylparaben and benzylparaben shift the steady-state inactivation curve 2- and 3-times more than propylparaben, respectively. Parabens are blockers of hNa_V1.2 channels, sharing the mechanism of action of most of sodium channel blocking antiseizure drugs. The potency of this inhibition increases with the size of the lipophilic alcoholic residue of the ester group. These results provide a basis for rational drug design directed to generate new potential anticonvulsant agents.