Parkinson's disease (PD) is the second most common neurodegenerative disorder. Androst-5-ene-3β, 17β-diol (ADIOL), an estrogen receptor (ER) β agonist, was found to induce a transrepressive mechanism, which selectively amend the extent of neuroinflammation and, in turn, neurodegeneration; nevertheless, its effect on PD has not yet been revealed. In consequence, our study was designed to examine the possible neuroprotective effect of ADIOL against a rotenone (ROT)-induced PD in rats. Reduction in the nuclear factor-kappa B (NF-κB) levels and the expression of down-stream inflammatory mediators was detected in the SN upon pre-treatment with ADIOL at the dose of 0.35 mg/kg/day. Likewise, light microscopy (LM) examination showed improvement in the number of viable neurons in the SN pars compacta (SNpc). In conclusion,the current study confirmed the ability of ADIOL to reduce neuroinflammation and, in turn, neurodegeneration process as well as motor impairment in PD.