Objectives: The inflammatory response is critically important in acute pancreatitis (AP). Systemic immune-inflammation (SII) index and systemic inflammation response index (SIRI), which are novel inflammatory markers, have been linked to determining outcomes in various diseases. The goal of the current study was to examine the relation of the SII index and SIRI with disease severity and acute kidney injury (AKI) in subjects with AP. Methods: A total of 332 subjects with AP were analyzed retrospectively. SII index was calculated using the formula; platelet (P)×neutrophil (N)/lymphocyte (L), while SIRI was calculated as N × monocyte (M)/L count. Multivariate regression (MR) was done to determine the independent risk factors for AKI and severe AP (SAP). Results: Statistical analyses showed that both median SII index and median SIRI increased gradually with higher AP severity (p < 0.001). Both SII index and SIRI were higher in subjects with AKI compared to controls (p < 0.001). Using MR analysis, the SII index was found to independently predict both SAP (OR = 1.004, 95% CI: 1.001–1.008, p = 0.018) and AKI (OR = 1.005, 95% CI: 1.003–1.008, p < 0.001). ROC analysis showed that the SII index could accurately differentiate SAP (AUC = 0.809, p < 0.001) and AKI (AUC = 0.820, p = 0.001) in patients with acute pancreatitis. ROC analysis also showed that SIRI could also accurately differentiate SAP (0.782, p < 0.001) and AKI (AUC = 0.776, p = 0.001). Conclusions: SIRI and the SII indexes can be used as potential biomarkers in predicting both disease severity and AKI development in subjects with AP.