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Background: Acute cholecystitis, a leading cause of urgent surgical intervention, poses challenges in predicting severity and operative complexity. This study characterized the immuno-inflammatory profile distinguishing acute from chronic cholecystitis and assessed whether blood-derived ratios—neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte (PLR)—correlate with histologic severity and surgical difficulty. Methods: The study retrospectively analyzed 759 patients undergoing cholecystectomy from 2016 to 2024. Inflammatory indices from preoperative bloodwork were compared across histopathologic subtypes (catarrhal, phlegmonous, gangrenous), clinical features, and surgical outcomes, including conversion to open procedure. Logistic regression and ROC analyses identified predictors of acute inflammation and conversion. Results: Acute cholecystitis patients showed elevated NLR (7.0 vs. 3.1), MLR (0.44 vs. 0.26), and PLR (194 vs. 142; all p < 0.001). NLR was the only independent predictor of acute disease (OR = 1.29, 95% CI 1.203–1.390, p < 0.001), with superior discrimination (AUC = 0.806, cut-off = 3.56; sensitivity 73.1%, specificity 80.4%). NLR and PLR rose progressively from catarrhal to phlegmonous and gangrenous subtypes (p < 0.05), mirroring conversion rates (0% catarrhal, 3.2% phlegmonous, 10.5% gangrenous; p = 0.001). Conclusions: Routine hematologic ratios capture systemic immune activation in acute cholecystitis, reflecting histologic severity and operative risk. NLR, integrating innate and adaptive immune dynamics, offers a practical biomarker for preoperative risk stratification in acute care surgery.