This study aimed to elucidate the potential causal relationship between 4,907 plasma proteins and the risk of gastric cancer using a two-sample Mendelian randomization approach. We utilized genome-wide association study (GWAS) data to perform two-sample Mendelian randomization analyses, treating the 4,907 plasma proteins as exposure factors and gastric cancer as the outcome. Instrumental variables for plasma proteins were selected based on strongly correlated SNPs identified through data processing and screening of the GWAS data provided by the deCode database. We employed a set of statistical methods centered on inverse variance weighting (IVW) for Mendelian randomization analysis to estimate the odds ratios (ORs) for the effects of these plasma proteins on gastric cancer susceptibility. According to the IVW method, 14 plasma proteins were associated with gastric cancer (p < 0.005). Specifically, CHST15 (OR = 0.7553, 95% CI = 0.6346 - 0.8988), L1CAM (OR = 0.7230, 95% CI = 0.5876 - 0.8896), FTMT (OR = 0.8246, 95% CI = 0.7241 - 0.9391), and PMM2 (OR = 0.5767, 95% CI = 0.3943 - 0.8433) were negatively correlated with GASTRIC CANCER, whereas ABO (OR = 1.1868, 95% CI = 1.0638 - 1.3240), FAM3D (OR = 1.2109, 95% CI = 1.0850 - 1.3515), FAM3B (OR = 1.2988, 95% CI = 1.0953 - 1.5402), ADH7 (OR = 1.3568, 95% CI = 1.1044 - 1.6670), MAP1LC3A (OR = 1.3704, 95% CI = 1.1194 - 1.6778), PGLYRP1 (OR = 1.4071, 95% CI = 1.1235 - 1.7623), PDE5A (OR = 1.7446, 95% CI = 1.2693 - 2.3978), GLUL (OR = 3.1203, 95% CI = 1.5017 - 6.4839), NFE2L1 (OR = 3.1759, 95% CI = 1.6163 - 6.2402), and MAFG (OR = 3.1945, 95% CI = 1.5329 - 6.6575) were positively correlated. Convergent results from Weighted Median and MR-Egger analyses confirmed these associations. Reverse Mendelian randomization analysis indicated that gastric cancer does not significantly alter the levels of these 14 plasma proteins (p > 0.05). Sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, confirmed the robustness and reliability of our findings without significant bias. Pathway enrichment analysis of gene expression associated with these 14 plasma proteins, using GO and KEGG pathways, revealed that CHST15, L1CAM, FTMT, and PMM2 may serve as protective factors against gastric cancer, while ABO, FAM3D, FAM3B, ADH7, MAP1LC3A, PGLYRP1, PDE5A, GLUL, NFE2L1, and MAFG may contribute to gastric cancer pathogenesis. These results highlight the complex biological interactions between plasma proteins and tumorigenesis, providing valuable insights for preventive and therapeutic strategies in gastric malignancy management.© 2025. The Author(s).