Background: Coronary collateral circulation (CCC) plays a crucial protective role in patients with chronic total occlusion (CTO), mitigating ischemia and improving long-term outcomes. However, the degree of collateral vessel development varies substantially among individuals. Systemic inflammatory and nutritional status may influence this variability. The Naples Prognostic Score (NPS) is a composite index reflecting these parameters, yet its relationship with CCC remains incompletely defined. Methods: We retrospectively analyzed 324 patients with angiographically confirmed CTO at Selçuk University Faculty of Medicine between 2014 and 2025. Coronary collaterals were graded using the Rentrop classification, and patients were categorized as having poor (grades 0–1) or good (grades 2–3) collaterals. The NPS was calculated using serum albumin, cholesterol, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio. Baseline clinical and laboratory data were compared between groups. Univariate and multiple binary logistic regression analyses were performed to identify independent predictors of collateral development. Results: Of the 324 patients, 208 (64.2%) had poor and 116 (35.8%) had good collateral circulation. Patients with good collaterals had higher body mass index, HDL Cholesterol (HDL-C), and triglyceride levels, and significantly lower NPS values compared with those with poor collaterals (p < 0.05 for all). In multiple binary logistic regression analysis, HDL-C (OR 1.035; 95% CI 1.008–1.063; p = 0.011) and NPS (OR 0.226; 95% CI 0.130–0.393; p < 0.001) emerged as independent predictors of well-developed collaterals. Conclusions: Both NPS and HDL-C are independently associated with the degree of coronary collateral circulation in CTO patients. These findings highlight the interplay between systemic inflammation, nutritional status, lipid metabolism, and vascular adaptation. As simple and routinely available measures, NPS and HDL-C may serve as practical tools for risk stratification and identifying patients at risk of inadequate collateral formation. Prospective studies with functional assessments of collateral flow are warranted to confirm these associations and explore potential therapeutic interventions.