PURPOSE: Parkinson's disease (PD) disrupts the regulation of neurotransmitters in the brain, causing patients to experience not only motor symptoms but also non-motor symptoms such as depression. 6-shogaol (6S) is a potential neuro-nutraceutical derived from ginger, and is known to ameliorate motor symptoms by suppressing inflammation in PD mice. In this study, we investigated whether 6S can attenuate motor symptoms and depression-like behaviors through neurotransmitter regulation and to elucidate which neurotransmitters are intimately correlated with these effects. METHODS: C57BL/6 J mice were injected with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 5 d to induce PD. 6S was administered via oral gavage for 11 d, including the MPTP injection period. RESULTS: 6S alleviated MPTP-induced motor symptoms and depression-like behaviors. MPTP injection decreased the levels of seven neurotransmitters in the striatum and four neurotransmitters in the hippocampus. Administration of 6S increased striatal dopamine, serotonin, and norepinephrine levels and hippocampal dopamine, norepinephrine, serotonin, and γ-aminobutyric acid levels. Moreover, correlation analysis shown that the motor symptom improvement effect of 6S was associated with striatal dopamine, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid levels. The effect of 6S on depressive-like behavior was significantly correlated with striatal dopamine metabolites and serotonin and hippocampal dopamine, norepinephrine, and serotonin. Immunohistochemistry showed that 6S upregulated the expression of the vesicular monoamine transporter 2, which was reduced by MPTP in the striatum and hippocampus. CONCLUSION: This study demonstrated that 6S improved motor symptoms and depression-like behaviors by regulating the release of monoamine neurotransmitters.