Introduction: Zonisamide (ZA) is a new drug that has been shown to be effective against motor damage in Parkinson's disease. However, the behavioral effect of ZA has not been described in male and female of rats. The aim of this study was to evaluate sexually dimorphic effects of ZA on behavioral locomotor activity in a rat model of Parkinson's disease. Materials & Method: 48 adult Wistar rats (24 male and 24 female) were randomly divided into eight groups, consisting of four groups of each sex: 1) sham group 2) PD group (Parkinson's model) 3) ZA group (vehicle) and 4) PD plus ZA group (Parkinson's model with ZA treatment). Parkinson's disease was administered by an injection of 6-hydroxydopamine (6-HD) into medial forebrain bundles. The drug was orally administered at a dose of 50 mg / kg every 24 hours for 7 days after surgery. The behavioral effects of apomorphine-induced rotation and spontaneous motor tests (elevated body swing, cylinder, and footfault test) were investigated in rats of both sexes. Results: ZA decreased contralateral rotations in male and female rats compared to the negative control group (p < 0.05) that is correlated with cell loss. ZA improves spontaneous motor tests in both sexes, and this finding is statistically significant. In the PD plus ZA group, the male and female comparisons demonstrated that step through latency in female was higher than that of the male (p <0 .001). Conclusion: These findings suggest that ZA has positive effects not only on motor and memory function but also on histological symptoms such as cell death in rat PD models.