Objective: To investigate the value of dynamic monitoring of serum interleukin (IL)-33 and tumor necrosis factor (TNF)-α levels in the early diagnosis, severity assessment and prognosis of acute pancreatitis (AP) combined with abdominal CT radiomics and intestinal microbiota data. Methods: A total of 170 AP patients were admitted immediately after the onset of the disease and divided into MAP group (85 cases) and SAP group (85 cases). The levels of serum IL-33, TNF-α, IL-6, and HMGB1, as well as the expression of miRNA-155 in extracellular vesicles (EVs), were dynamically monitored at multiple time points (0 h, 6 h, 12 h, 24 h, 3 d, 5 d, 7 d, 14 d) after admission. Abdominal CT radiomics analyzed the texture characteristics of pancreatic necrosis, and stool samples collected at admission were metagenomic sequencing of the gut microbiome. The Acute Pancreatitis Severity Bedside Index (BISAP) score is calculated within 48 hours of admission. Multivariate regression analysis assessed the independent effects of various factors on the prognosis of mortality groups. Results: Serum IL-33 and TNF-α levels in SAP patients were significantly higher than those in MAP patients (p < 0.05) at all time points, peaked on day 3, and decreased with treatment. The levels of these cytokines in patients with SIRS were also higher than in patients without SIRS (p < 0.05). The serum IL-33, TNF-α levels and BISAP scores in the mortality group were higher than those in the survival group (p < 0.05). Multivariate regression analysis showed that serum IL-33 (OR = 3.21, 95% CI: 1.12–9.23, p = 0.03), TNF-α (OR = 4.05, 95% CI: 1.37–11.96, p = 0.01), and BISAP score (OR = 5.67, 95% CI: 1.83–17.54, p < 0.01) were independent prognostic risk factors. Spearman correlation analysis showed that serum IL-33 and TNF-α levels were positively correlated with BISAP scores(r = 0.68, p < 0.01; r = 0.73, p < 0.01). Conclusion: Dynamic monitoring of serum IL-33 and TNF-α levels combined with BISAP score has important clinical value for early diagnosis, severity assessment, treatment guidance and prognosis evaluation of AP, and provides a basis for accurate diagnosis and treatment.