Objective To investigate the feasibility of using plasma methylation of ZNF582 in conjunction with ELMO1 to diagnose gastric cancer (GC). Methods Plasma samples from 47 GC patients and 63 individuals without relevant gastrointestinal diseases were collected as the experimental and control groups, respectively, at The Affiliated Jiangning Hospital of Nanjing Medical University. Methylation markers ZNF582 and ELMO1 were quantified using Quantitative Real-time Polymerase Chain Reaction (qPCR). Results The methylation level of ZNF582 in the GC group was significantly higher than that in the control group (P＜0.0001), and the ELMO1 methylation level was significantly elevated in the GC group compared to the control group (P＜0.05). The sensitivity of ELMO1 correlated significantly with the depth of invasion and staging of GC, with higher sensitivity in stages T3-T4 compared to T1-T2 (12.5% vs 51.6%), and in stages Ⅲ-Ⅳ compared to Ⅰ-Ⅱ (22.7% vs 52%). Compared to stages Ⅰ-Ⅱ GC, stages Ⅲ-Ⅳ GC showed higher sensitivity for ZNF582 (27.3% vs 56.0%). When methylation of ZNF582 and ELMO1 were combined, sensitivity increased, compared to individual detection. Additionally, the methylation of ZNF582 and ELMO1 demonstrates higher sensitivity for T3-T4 and Ⅲ-Ⅳ stages than for T1-T2 and Ⅰ-Ⅱ stages (31.2% vs71.0%, 36.4% vs 68.0%, respectively), with statistically significant differences P ＜ 0.05). The ROC curve analysis revealed that area under curve (AUC) values for methylation of ZNF582 and ELMO1 in distinguishing the GC group from the control group were 0.7270 (95%CI: 0.6277-0.8263) and 0.7789 (95%CI: 0.6398-0.9180), respectively. When combined, the AUC increased to 0.8990 (95%CI: 0.8411-0.9570). Conclusion The plasma methylation levels of ZNF582 and ELMO1 are higher than those in the control group, exhibiting heightened sensitivity in detecting GC, and showing an association with clinical staging. Combining these two methylation markers enhances the precision of GC diagnosis. Therefore, the utilization of plasma ZNF582 and ELMO1 in diagnosing GC and predicting pathological staging holds potential clinical significance