BACKGROUND: Apart from being a primary cause of morbidity and mortality globally, gastrointestinal (GI) disorders also contribute significantly to the cost of healthcare. In patients with GI diseases, the systemic inflammatory response index (SIRI) is not often used as a marker of systemic immune inflammation to assess mortality-associated risk from malignant neoplasms or all causes. Therefore, the objective of this study was to elaborate on the link between SIRI and all causes and malignant neoplasm mortality in patients with GI disorders. METHODS: Retrospective analysis was performed using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018. Restricted cubic spline (RCS) plots and multivariate Cox proportional hazards regression were used to examine the relationship between SIRI and GI patient mortality from malignant neoplasms and all causes. Data on survival were shown using Kaplan-Meier (KM) survival curves, and these correlations were further explored by subgroup and interaction analyses. Receiver operating characteristic (ROC) curves were generated to evaluate the specificity and sensitivity of SIRI in predicting mortality among patients with GI diseases. RESULTS: This study included 4,137 GI patients who were followed comprehensively over 20 years, during which 165 malignant neoplasm mortality and 713 all-cause mortalities were recorded. A nonlinear association between all-cause mortality and SIRI was observed, whereas in GI patients, a linear relationship was identified between SIRI and cancer-related death. The hazard ratio (HR) was 1 at a SIRI level of 1.114, indicating the low-to-high mortality risk change. Participants in the highest quartile (Q4) in the fully adjusted model (model 3) showed a significantly greater likelihood of death from both malignant neoplasms and all-cause relative to those in the lowest quartile (Q1). The mortality HR for malignant neoplasms was 1.74 [95% confidence interval (CI): 1.08-2.82], whereas the HR for all-cause mortality was 2.50 (95% CI: 1.95-3.20). Furthermore, subgroup analysis revealed that higher SIRI was linked with a higher malignant neoplasm mortality risk among male, low-income, smoking, and drinking GI patients. Comparing SIRI to the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), the ROC curve analysis showed that SIRI had better diagnostic effectiveness. Interaction study verified that SIRI is an independent variable that significantly increases the probability of death from both all-cause and malignant neoplasms. CONCLUSIONS: The nonlinear positive correlation between the SIRI and the mortality from malignant neoplasms and all-cause in GI patients is highlighted by this study. Elevated SIRI levels were significantly linked to a higher mortality rate from GI disorders, including malignant neoplasms and all-cause. Thus, in GI patients, SIRI can be used as a prognostic marker for mortality and long-term health outcomes prediction.