Purpose There is growing evidence that autophagy-related gene 5 (ATG5) is involved in neural development, neuronal differentiation, and neurodegenerative diseases. The purpose of this study was to investigate the association between ATG5 gene single-nucleotide polymorphisms (SNPs) and Parkinson’s disease (PD) in the Han population. Methods A case–control study was conducted in 120 PD patients and 100 healthy volunteers. MassArray platform was used to analyze polymorphisms in three different regions of ATG5 gene (rs510432, rs573775 and rs17587319). In the included subjects, 50 PD patients and 50 healthy volunteers were selected, and the plasma ATG5 concentration was detected by enzyme-linked immunosorbent assay (ELISA). The allele and genotype frequencies of SNPs were assessed using the SHEsis program. Results We found a significant correlation between rs17587319 and PD, and the subcomponent showed a high correlation between rs17587319 with cognitive impairment and age at onset in PD patients. At the same time, the total plasma ATG5 level of PD patients and the plasma ATG5 expression level of early-onset Parkinson’s disease (EOPD) patients were significantly higher than the control group, while there was no significant difference of ATG5 expression between late-onset Parkinson’s disease (LOPD) patients and the control group. Conclusion These findings suggest that genetic variations in the ATG5 gene and low levels of the ATG5 protein are associated with susceptibility to PD and with cognitive impairment in PD patients. ATG5 could be a potential biomarker to assess the severity and prognosis of PD.