Inflammation plays a significant role in the occurrence and development of acute kidney injury (AKI). Evidence regarding the prognostic effect of the systemic immune-inflammation index (SII) in critically ill patients with AKI is scarce. The aim of this study was to assess the association between SII and all-cause mortality in these patients. Detailed clinical data were extracted from the Medical Information Mart for Intensive Care Database (MIMIC)-IV. The primary outcome was set as the in-hospital mortality. A total of 10,764 AKI patients were enrolled in this study. The restricted cubic splines analyses showed a J-shaped curve between SII and the risk of in-hospital and ICU mortality. After adjusting for relevant confounders, multivariate Cox regression analysis showed that both lower and higher SII levels were associated with an elevated risk of in-hospital all-cause mortality. A similar trend was observed for ICU mortality. In summary, we found that the SII was associated in a J-shaped pattern with all-cause mortality among critically ill patients with AKI. SII appears to be have potential applications in the clinical setting as a novel and easily accessible biomarker for predicting the prognosis of AKI patients.