Parkinson's disease (PD) is a progressive degeneration of dopaminergic neurons in the substantia nigra, leading to the loss of dopaminergic tone in the striatum. Billions of dollars are spent around the world to address health issues due to neurodegeneration mediated memory loss and cognitive deficits. Hence, there is an urgent need to develop novel neuroprotective strategies to reduce the neurodegeneration.1‐methyl‐4‐pheneyl‐1,2,3,6‐terahydropriydine (MPTP) is a potent neurotoxin that causes selective loss of dopaminergic neurons and causing Parkinson's disease like symptoms. Acetylcholine (ACh) is a prominent neurotransmitter in the striatum and exerts part of its actions through nicotinic cholinergic receptors. Activation of these receptors has been associated with the enhancement of learning and certainly is instrumental in habitual use of nicotine. Dopamine release is modulated by activation of nicotinic receptors in the dorsal striatum. Nicotine can either protect neurons from neurodegeneration or induce oxidative stress, depending on its dose and degree of oxidative stress impairment. However, the relationship between nicotine and oxidative stress in the PD remains largely unknown. The purpose of this study was to determine the effect of nicotine on glutathione (GSH)‐centered antioxidant system and oxidative stress. Parkinson's disease animal model was induced in mice by systemic injection of MPTP and then we investigated the behavioral, neurochemical, biochemical and neuropathological hallmarks of the disease. Inflammation, oxidative stress, mitochondrial dysfunction, and altered GABA/Glutamate levels are associated with progressive nigrostriatal neurodegeneration. Nicotine in small dose significantly enhanced dopamine release, suggesting the improvement of the behavioral defect induced by MPTP, scavenged the free radicals, and altered the major endogenous antioxidant molecules and striatal GABA levels leading to neuroprotection. Thus, Nicotine can have therapeutic value due to its neuroprotective effects against various movement disorders. This will have far‐reaching effects in future therapeutics in terms of new treatment strategies.