To analyze the factors related to Helicobacter pylori (Hp) infection in patients with severe acute pancreatitis (SAP) and to observe the effect of Hp on SAP, and to provide a reference for future clinical prevention and treatment of Hp infection in SAP. A retrospective analysis was performed on 77 SAP patients admitted to Pingxiang People's Hospital between January 2020 and February 2022, with 33 Hp-infected individuals as the Hp-positive group and the other 44 patients being without Hp infection served as the Hp-negative group. First, the related factors of Hp infection in SAP patients were analyzed with multiple Logistic regression. Subsequently, the Acute Physiology and Chronic Health Evaluation II (APACHE II), Bedside Index for Severity in Acute Pancreatitis (BISAP) and Modified CT Severity Index (MCTSI) scores, as well as the levels of C-reactive protein (CRP), white blood cell (WBC), procalcitonin (PCT) and immunoglobulins A/M/G (IgA, IgM, and IgG) were recorded for inter-group comparisons. The adverse reactions and hospitalization time were also recorded. Besides, a six-month follow-up was carried out after discharge, and patients' quality of life was evaluated using the Short-Form 36 Item Health Survey (SF-36). Logistic regression analysis identified that history of Hp infection, long-term drinking, eating habits and history of biliary tract diseases were independent risk factors for Hp infection (all P<0.05). At 2 weeks after admission, higher APACHE II, BISAP and MCTSI scores were observed in Hp-positive group compared with Hp-negative group (all P<0.05). The Hp-positive group exhibited higher CRP, WBC and PCT levels while lower IgA, IgM and IgG levels during treatment compared to the Hp-negative group (all P<0.05). No difference was found in the incidence of adverse reactions between the two groups (P>0.05), but the hospitalization time of the Hp-positive group was significantly prolonged (P<0.05). The follow-up results determined better quality of life in the Hp-negative group, which resulted in higher SF-36 scores in various dimensions (P<0.05). The history of Hp infection, long-term drinking, eating habits, and history of biliary tract diseases are all independent risk factors for Hp infection. Hp infection exacerbates disease progression of SAP, adversely influences patients' recovery, impairs their immune function, and compromises their prognoses.