Background: The study aimed to evaluate the accuracy with which various nutritional and inflammatory indicators, including Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Systemic Immune-Inflammation Index (SII), Monocyte-to-Lymphocyte Ratio (MLR), Systemic Inflammatory Response Index (SIRI), and Prognostic Nutritional Index (PNI), can predict the severity of acute calculus cholecystitis. Methods: 109 cases of chronic calculus cholecystitis (CCC) and 130 cases of acute calculus cholecystitis (ACC), including 62 cases of acute simple cholecystitis (ASC), 35 cases of acute purulent cholecystitis (APC), and 33 cases of acute gangrenous cholecystitis (AGC), were encompassed in the retrospective cohort study. The patients' clinical information and inflammatory-immune markers were collected for analysis. Results: The optimal cut-off values for NLR, SIRI, SII, MLR, PLR, and PNI in distinguishing ACC from CCC were determined to be 2.499, 0.964, 593.5, 0.230, 148.0, and 141.3, respectively. NLR > 2.499 demonstrated the highest predictive capability, with an AUC of 0.896. Multivariate analysis indicated that NLR > 2.499 (OR: 4.69, p = 0.006) was the dominant factor in differentiating ACC from CCC. The optimal cut-off values for SII, SIRI, MLR, NLR, PLR, and PNI in distinguishing ASC from APC were 1098, 2.092, 0.304, 4.082, 191.1, and 135.3, respectively. SII > 1098 exhibited the highest predictive capability, with an AUC of 0.73. The optimal cut-off values for NLR, SIRI, MLR, SII, and PLR in differentiating APC from AGC were 7.232, 4.773, 0.557, 2417, and 221.5, respectively. NLR > 7.232 demonstrated the highest predictive capability, with an AUC of 0.826. Conclusion: Systemic inflammatory index and nutritional marker can serve as valuable indicators for predicting acute calculus cholecystitis and its severity. An elevated systemic inflammatory index and a declining nutritional marker suggest an increased risk of severe cholecystitis, warranting prompt and appropriate interventions.