Objective To investigate the effects of individualized therapy regimens guided by CYP2C19 genetic polymorphism testing and helicobacter pylori (Hp) resistance culture on Hp eradication rates, gastric acid suppression levels, adverse reactions, and quality of life(QoL). Methods A total of 98 patients diagnosed with Hp infection in the Department of Gastroenterology, Xuancheng People""s Hospital from January 2025 to July 2025 were selected. The treatment group (50 cases) underwent CYP2C19 genotyping and Hp resistance culture, and individualized regimens were formulated according to metabolic type and resistance profile. The control group (48 cases) received empirical triple or quadruple therapy. Eradication rate, gastric pH changes, inflammatory cytokine levels, incidence of adverse reactions, and QoL scores were compared between the groups. Results The eradication rate in the treatment group was significantly higher than that in the control group (94.00% vs. 77.08%, P＝0.018). On the 7th and 14th days after treatment, the gastric juice pH values in the treatment group were significantly higher than those in the control group (all P＜0.05), the reductions of interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) levels were significantly greater than those in the control group (all P＜0.05), the incidence of adverse reactions was significantly lower than that in the treatment group (8.33% vs. 21.74%, P＝0.047), the improvements of QoL scores was significantly better than that in the control group (P＜0.05). Conclusion CYP2C19 gene polymorphism testing combined with Hp resistance culture enables “precision acid suppression＋ targeted antibacterial therapy”, significantly improving Hp eradication rates, enhancing gastric acid suppression efficacy, reducing adverse reactions, and elevating QoL.