AIM: The investigation aimed to study the outcome of rosiridin in Parkinson's disease (PD) induced by rotenone (ROT) in rodents. METHODS: Rodents were randomized into IV groups and were induced with ROT followed by treatment with rosiridin. Group I-IV received saline as a vehicle, II-ROT (0.5 mg/kg S.C) for 28 consecutive days, III and IV- rosiridin 10 and 20 mg/kg orally with ROT. On completion of the experimental duration, behavioral investigations were carried out. Biochemical variables such as acetylcholinesterase (AChE), oxidative stress and antioxidants markers (Malondialdehyde-MDA, glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), anti-inflammatory (Interleukin-1 beta-IL-1β, IL-6, and tumor necrosis factor alpha-TNF-α), alteration in neurotransmitters (Serotonin-5-HT), norepinephrine, and dopamine-DA, along with metabolites such as 5-hydroxy indole acetic acid-5- HIAA),), mitochondrial complex I, II, IV, and caspase-3 activity were evaluated at the end of the experiment. Furthermore, molecular docking and dynamics were performed for target ligands. RESULTS: Rosiridin significantly restored the level of AChE, oxidative stress and antioxidants markers (MDA, GSH, SOD, and CAT), anti-inflammatory (IL-1β, IL-6, and TNF-α), alteration in neurotransmitters, mitochondrial complex I, II, IV, and caspase-3 activity. Rosiridin has a favorable negative binding affinity to AChE (-8.99 kcal/mol). The results of the molecular dynamics simulations indicate that proteins undergo a substantial change in conformational dynamics when binding to rosiridin. CONCLUSION: In this study, rosiridin may exhibit neuroprotective properties against the Parkinson's model for treating PD.