Gastric cancer, a common and severe malignancy, is associated with unfavorable outcomes and limited therapeutic options. The exploration of the potential link between plasma histone-modifying enzymes and gastric cancer through Mendelian randomization (MR) analysis offers an opportunity to identify new therapeutic targets and biomarkers. In this study, data on plasma histone-modifying enzymes were obtained from the International Working Unit Open genome-wide association studies project, and summary statistics of gastric cancer from the FinnGen study were analyzed. Forward and inverse MR were performed to determine the causal relationship between plasma histone-modifying enzymes and gastric cancer. The principal methodology for MR is the inverse variance weighted (IVW) method. Additionally, a sensitivity analysis was performed to determine the robustness of the findings. Finally, bioinformatics was used for the preliminary functional analysis. Our forward MR analysis revealed that the plasma Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L) was positively associated with gastric cancer risk, and the histone-lysine N-methyltransferase SETMAR (SETMAR) was negatively associated. Inverse MR analysis revealed that gastric cancer incidence was negatively correlated with the expression of plasma histone acetyltransferase KAT6A (KAT6A). These findings were consistent across different statistical methods and were deemed unlikely to have been distorted by horizontal pleiotropy. Furthermore, bioinformatics analysis indicated that ASH2L, SETMAR, and KAT6A are differentially expressed in various tumors and are significantly correlated with both the prognosis of gastric cancer and the infiltration of various immune cells. Thus, plasma histone-modifying enzymes may be causally linked to gastric cancer, and ASH2L, SETMAR, and KAT6A could play crucial roles as biomarkers and therapeutic targets in managing gastric cancer.© 2024 The Authors. Published by Elsevier Ltd.