Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H 3 receptors (H 3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H 3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the ( S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide ( 1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, ( R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide ( 2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer ( 1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier ( R)-enantiomer ( 3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its ( S)-enantiomer ( 4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the ( R)-enantiomer ( 3) in MES model were significantly greater than those of the standard H 3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H 3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1– 6 revealed profound stereoselectivity at human H 3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1– 6 showed stereoselectivity in different convulsion models in male adult rats.