In order to investigate the mechanisms and therapeutic effects of valproate combined with lithium carbonate on mouse model of Parkinson's disease (PD), male C57BL/6 mice were injected into intraperitoneal with valproate (20 μg/ml) combined with lithium carbonate (10 μg/ml) for 7 days following 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (30 mg/kg) administration, and the effects on motor function were analyzed. Immunohistochemistry and Western blotting were used to detect alterations in the expression of PD biomarkers, including tyrosine hydroxylase (TH), and the level of autophagy was evaluated by the detection of microtubule-associated protein light chain 3 (LC3). In addition, the levels of monoamine neurotransmitters were measured in the striatum using high performance liquid chromatography (HPLC). After MPTP exposure, all groups manifested decreased rolling bar latency and spontaneous activity, in addition to increased pole-climbing time. The combined treatment group exhibited a recovery of rolling bar latency and pole-climbing time. The number of dopaminergic neurons in the substantia nigra following MPTP treatment was higher in the combined treatment group compared with the positive control group (p = .003). Immunoreactivity for LC3 was higher in the combined treatment group than in the controls (p = .003). The concentrations of both striatal dopamine and the dopamine metabolite dihydroxyphenyl acetic acid (DOPAC) were decreased in both MPTP-treated groups compared with the controls. The loss of DOPAC was less severe in the combined treatment group relative to the positive control group (p = .001). Therefore, we infer that valproate combined with lithium carbonate can rescue dopaminergic neurons and ameliorate the loss of DOPAC following MPTP treatment, likely via activation of autophagic/lysosomal pathways.