Studies have shown that Helicobacter pylori ( H. pylori ) infection can induce chronic inflammation and immune responses in the gastric mucosa, potentially contributing to the development of lymphoma. To explore the association between H. pylori and Diffuse large B-cell lymphoma (DLBCL), the Mendelian randomization (MR) analysis was employed. Additionally, the CIBERSORT algorithm was utilized to investigate the immune microenvironment in DLBCL associated with H. pylori for novel biomarkers identification. A two-sample MR analysis confirmed a bidirectional causal relationship between H. pylori UREA antibody and DLBCL incidence. The primary method used (IVW: OR=1.323, 95 % CI 1.046-1.675, P -value=0.02 < 0.05) indicated a significant positive causal association without evidence of heterogeneity or horizontal pleiotropy. A total of 881 differentially expressed genes (DEGs) were identified when comparing DLBCL patients resistant versus sensitive to H. pylori eradication treatment from GSE182362. The hub genes EDNRB, ACTG2, SST, CCL2, COL11A1, SELE, ALB, DUOX2, BPIFB1, and CXCL6 exhibited enrichment within the immune microenvironment context. CCL2 exhibited significant correlations with M1 macrophages, M2 macrophages, Neutrophils, T cells CD4 memory resting and Plasma cells. These findings elucidate the causal association between H. pylori UREA antibody levels and DLBCL, while underscoring the potential for targeted therapy in H. pylori -positive patients diagnosed with DLBCL.