Oxidative stress is one of the mechanisms implicated to play a significant role in the pathophysiology of Parkinson's disease. Previously, we showed that an aqueous extract of Selaginella delicatula (SDAE) offered robust neuroprotection against rotenone (ROT) in a Drosophila model. In furtherance in the present study, we validated the neuroprotective efficacy of SDAE in a chronic ROT exposure model in mice. Initially, we assessed the propensity of SDAE to modulate the levels of endogenous markers in striatal region of mice. Subsequently, the neuroprotective efficacy of SDAE (100 mg/kg bw, 21 d) to mitigate ROT-induced striatal motor deficits, oxidative stress, and neurotoxicity was examined employing a co-exposure paradigm. We found significant attenuation of ROT-induced motor deficits (stride length and landing foot spread distance) among mice given SDAE supplements. Biochemical analysis revealed that ROT-induced elevation in the levels of oxidative markers in cytosol/mitochondria of striatum were normalized with SDAE supplements. In addition, SDAE also restored the ROT-induced elevation in the levels of oxidized and nitrated proteins. Further, SDAE also restored the activities of acetylcholinesterase and butyrylcholinesterase indicating its effect on cholinergic function. While ROT exposure caused significant perturbations in the activity levels of mitochondrial electron transport chain enzymes (complex I/II), membrane potential and activity of ATPases, these functions were restored to normalcy among mice receiving SDAE suggesting its effects on mitochondrial function. Since these data corroborate our previous findings in Drosophila system, we propose that the neuroprotective property of SDAE may be largely attributed to the antioxidant properties and its ability to attenuate mitochondrial dysfunction. However, studies employing dopaminergic cell models would enable us to identify specific molecular mechanism, by which SDAE exerts neuroprotective action.