Introduction: In Parkinson's disease (PD), compelling data indicate a functional link between adenosine/dopamine receptors and the progression of the neurodegenerative process. The present study was carried out to evaluate the effect of the non-selective adenosine receptor (ADR) antagonist caffeine, as well as the selective antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an ADRsA(1) antagonist, and ((E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002), an ADRsA(2A) antagonist, on the prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice. Material and methods: Mice were allocated to five groups: group I control group; group II: MPTP group, received four injections of MPTP (20 mg/kg, i.p.) at 2 h intervals; groups III, IV, V: received MPTP and i.p caffeine (20 mg/kg/day) or DPCPX (5 mg/kg/day) or KW-6002 (10 mg/kg/day) starting one week before MPTP injection and continuing for 2 weeks. Results: Therapy with caffeine or KW-6002 not only led to the reversibility of movement dysfunction and increased the concentrations of dopamine and ATP levels (p < 0.05), but also, ameliorates the dopaminergic neuron loss and restored the mtDNA and nDNA integrity (p < 0.05). Furthermore, in passive avoidance test, caffeine and DPCPX significantly (p < 0.05) reversed the MPTP-induced memory deficits, whereas the specific ADRsA2A antagonist did not. Conclusions: The current results provide evidence that blockade of both ADRsA(1) and ADRsA(2A) has therapeutic implications in alleviating MPTP-induced motor and cognitive dysfunction and might be a promising candidate for treatment of PD.