Background: Naples Prognostic Score (NPS), a composite index incorporating inflammatory and nutritional markers, has emerged as a potential prognostic tool in various cardiovascular conditions; however, no meta-analysis has yet pooled the available evidence to comprehensively assess its prognostic utility. Objectives: To evaluate the association of NPS with clinical outcomes, including all-cause mortality, in-hospital mortality, no-reflow (NR) phenomenon, and left ventricular ejection fraction (LVEF), in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Methods: MEDLINE, Cochrane, and EMBASE databases were searched for studies comparing high and low NPS groups in ACS patients undergoing PCI. Random-effects models were used to pool risk ratios (RR) for binary outcomes and mean differences (MD) for continuous outcomes. Heterogeneity was assessed with I² statistics. Statistical analyses were performed using Review Manager 5.4, and R, version 4.2.2. Results: We included seven studies comprising 13 268 patients, with 5628 (42.4%) patients in the low NPS group. Low NPS was significantly associated with decreased all-cause mortality (RR: 0.42; 95% CI: 0.32–0.55; I² = 48%) and decreased incidence of NR (RR: 0.60; 95% CI: 0.40–0.88; I² = 83%). Patients with low NPS also had higher LVEF (MD: −2.69%; 95% CI: −3.41 to −1.97; I² = 99%). No significant difference was observed in in-hospital mortality (RR: 0.54; 95% CI: 0.28–1.05; I² = 94%). Conclusion: In ACS patients undergoing PCI, elevated NPS was associated with worse clinical outcomes. These findings support the use of NPS as a practical, biomarker-based tool for risk stratification in this population.