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Objective: To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease (PD). Methods: Nine literature databases in domestic and abroad were searched by computer, and the search deadline was November 2, 2020. The randomized controlled trials (RCT) using donepezil to treat the cognitive decline in patients with PD were screened. The MMSE (Mini-Mental State Exam) scores, MoCA (Montreal Cognitive Assessment) scores and adverse events of the included RCTs were extracted. Meta-analysis was implemented with RevMan 5.3 software, and the subgroup analyses were conducted to evaluate the effects of mean age and mean course of disease on the MMSE scores. Results: 14 RCTs with 1263 patients were selected, including 646 cases in the experimental group and 617 cases in the control group. There were 1209 effective patients who completed MMSE score, including 612 in the experimental group and 597 in the control group. Meta-analysis results showed that MMSE scores in the experimental group were higher than that in the control group after using donepezil intervention, and the difference was statistically significant [SMD=0.55, 95％ CI (0.24, 0.87), P=0.0006]. It was also found that the MoCA scores of experimental group were higher than that of control group after using donepezil intervention, and the difference was statistically significant [SMD=1.25,95％ CI (0.79, 1.72),P<0.00001]. Subgroup analysis showed that donepezil improved MMSE scores in different subgroups, and the difference between each group was statistically significant. There was no heterogeneity in the subgroup of mean age lower than 65 years, and the heterogeneity existed between the subgroup of mean course of disease lower than 3 years and the subgroup of mean course of disease larger than or equal to 3 years. For adverse events, the incidence of adverse events in the experimental group was 22.18％. There was no heterogeneity between the included studies (I2=0％), and the difference was not statistically significant [RR=1.18, 95％ CI (0.95, 1.47), P=0.14]. Conclusion: The results of meta-analysis showed that donepezil can improve the cognitive decline in patients with Parkinson's disease significantly, and it has good safety.