Background: Over 15 million people died globally from acute coronary syndrome (ACS) in 2019, with individuals under 70 years old accounting for 40% of these untimely fatalities. Aim: The current study aimed to assess effectiveness of novel inflammatory index in prediction of coronary artery disease severity in Egyptian patients with acute coronary syndrome. Methods: This prospective cross-sectional study was conducted on a total of 100 patients with acute coronary syndrome. Systemic immune inflammation index (SII), systemic inflammation response index (SIRI) and systemic immune-inflammation response index (SIIRI) and systemic immune-inflammation response index were calculated. Results: SII ranged from 83.3 to 5310.8 with a mean value of 880.2 ± 778.62. SIRI ranged from 0.39 to 14.35 with a mean value of 3.6 ± 2.96. SIIRI ranged from 83.3 to 4632 with a mean value of 1007.3 ± 877.86. SII, SIRI and SIIRI were significantly lower in Syntax ≤ 20 group than Syntax >20 group (P value < 0.05). Conclusion: Patients with acute coronary syndrome (ACS), including STEMI, NSTEMI, and unstable angina (UA), exhibited elevated levels of the novel inflammatory marker SIRI. This index could serve as an effective inflammatory biomarker for prognostic assessment in ACS patients, demonstrating superior predictive ability for cardiac events and long-term outcomes. Consequently, measuring SIRI presents a new opportunity to implement more aggressive treatment strategies for high-risk populations.