Parkinson’s disease occurs due to loss of dopaminergic neurons, which alters the behavioural changes. The present study evaluates the effect of exercise on neurodegeneration against Parkinson’s disease (PD) rat model and postulates its effect on novel molecular pathway. Rotenone was administered at 1 mg/kg s.c. every 48 h for 18 days for the in­duction of PD and exercise was given to rats for a period of 2 weeks after the confirmation of PD. Moreover, PD rats also received CGS 21680 (adenosine A2A receptor agonist, 0.5 mg/kg, i.p.) with exercise for a period of 2 weeks after confirmation of PD. The effect of exercise was assessed for motor and cognitive function in PD rats. The level of inflammatory cytokines and neurotransmitters was estimated in brain tissue of PD rats. Data of investigation reveal that exercise attenuates cognitive and motor function in PD rats, the exercise + CGS 21680 group shows reverse in the behavioural changes compared to exercise-treated PD rats. The level of inflammatory cytokines and neurochemical level ameliorated in the exercise-treated group compared to the PD group of rats, which is reversed in the exercise + CGS 21680 group. In conclusion, exercise protects neurodegeneration in PD rats by reducing aggregation of a-synuclein and activity of adenosine 2A receptor.