Recent studies suggest that palmitoylation may influence proteins involved in neurotransmission and neurodegenerative changes, such as pathological α-synuclein. However, the role of palmitoylation in Parkinson's disease (PD) has not been systematically investigated. Additionally, findings on DNA methylation changes and PD-associated gene expression remain inconsistent. This study aims to explore the causal relationship and mechanisms between palmitoylation genes, DNA methylation, and PD using Mendelian Randomization (MR). This study employed two-sample MR analysis, summary-data-based Mendelian Randomization (SMR) analysis, and mediation analysis, utilizing PD GWAS data from the Finngen database, palmitoylation genes data from the eQTLGen database, and DNA methylation data from the GoDMC database. First, a two-sample MR analysis was used to evaluate the causal relationship between the palmitoylation genes and PD. Then, the SMR method was applied to validate the association between gene expression and PD. Finally, mediation analysis was conducted to explore the mediating effect of DNA methylation on the relationship between expression of palmitoylation genes and PD. Our study found a significant positive correlation between high expression of the ZDHHC13 gene and increased PD risk. Each 1 standard deviation increase in ZDHHC13 expression was associated with a 24.20% increase in PD risk. Further DNA methylation analysis identified two key methylation sites (cg00161556 and cg27379915), which indirectly influenced the occurrence of PD by regulating the expression of the ZDHHC13 gene. Mediation effect analysis revealed that the methylation sites cg00161556 and cg27379915 indirectly promoted the development of PD by regulating the expression of the ZDHHC13 gene, with the mediation effect of ZDHHC13 gene expression accounting for 63.72% and 57.61% of the total effect, respectively. Sensitivity analysis and SMR analysis supported our findings, indicating high statistical robustness. This study highlights the role of DNA methylation in regulating ZDHHC13 during PD progression, suggesting potential clinical applications such as ZDHHC13 as a biomarker or therapeutic target for early PD diagnosis and treatment.