Parkinson's disease (Powers et al.) is a slowly progressive neurodegenerative movement disorder and it is the second most common neurodegenerative disorder after Alzheimer's disease. Several hypotheses have been proposed to explain the pathogenesis of PD, of which apoptotic cell death, neuroinflammation and oxidative stress are the most prevalent. Tetramethylpyrazine (TMP) is the major bioactive component of Ligusticum wallichii Franchat (ChuanXiong), Family Apiaceae, which exhibits anti-apoptotic, anti-inflammatory and antioxidant roles. In the present study, the possible neuroprotective effect of TMP against rotenone-induced model of PD in rats was investigated and the possible mechanisms were elucidated. Results showed that systemic rotenone administration significantly impaired rats' movement and induced postural instability, compared to the control group. Co-administration of TMP significantly improved rats movement and attenuated postural instability in rotenone-treated rats. Moreover, rotenone-treated rats exhibited altered midbrain histology, evidenced by severe hemorrhage, hyalinosis and blood vessels' congestion in addition to a significant loss of tissue histo-architecture, where the neurons appeared hyperchromatic, lost the round form of normal ones and phantom nuclei appeared scattered in the field. Co-treatment with TMP showed restoration of normal histological structure in the midbrain and the global appearance of the tissue in sections co-treated with TMP was closer to normal with apparent increased number of normal neurons as compared to rotenone-treated rats. Immunohistochemical staining of the midbrain sections showed that rotenone increased caspase-3 expression compared to the control, while co-treatment with TMP reduced caspase-3 expression compared to rotenone treated rats. In conclusion, the present study demonstrated that TMP has neuroprotective effects in rotenone-induced PD. Therefore, TMP can be a promising candidate for further investigations in other neurodegenerative disorders.