Objective To investigate the neuroprotective effect of resveratrol (RV) in mice with Parkinson's disease (PD) and its possible mechanisms.Methods A total of 48 mice were divided into CON group, MPTP group, RV+MPTP group, and EX527+RV+MPTP group, with 12 mice in each group. Intraperitoneal injection of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish the mouse model of PD, and RV gavage and intraperitoneal injection of the silent information regulation 2 homolog 1 (SIRT1) specific inhibitor EX527 were given. Immunofluorescence assay and Western blot were performed to measure the expression of related proteins.Results After administration of RV, compared with the MPTP group, the RV+MPTP group showed significantly increased protein expression of SIRT1 and p-AMP-activated protein kinase (AMPK), significantly reduced protein expression of cleaved caspase 3, significantly reduced TH-positive neuronal loss in the substantia nigra, and significantly increased expression of TH protein (all P<0.01). The administration of EX527 inhibited the above effects of RV and caused a significant reduction in the protein expression of p-AMPK (P<0.01), as well as significantly increased protein expression of cleaved caspase 3 (P<0.01), significantly increased TH-positive neuronal loss in the substantia nigra, and significantly reduced expression of TH protein (P<0.001).Conclusions RV can activate the SIRT1/AMPK signaling pathway, regulate SIRT1 and AMPK, and thus reduce dopaminergic neuronal loss in the substantia nigra of mice treated with MPTP.