Introduction: The predictive role of serum bilirubin levels on the alteration of total ischemic burden expressed via frontal QRS-T angle change has never been studied in patients with acute coronary syndrome (ACS). In this study, we aimed to investigate the relationship between serum bilirubin levels and frontal QRS-T angle change after percutaneous coronary intervention (PCI) in ACS patients. Methods: Frontal QRS-T angle change was accepted as positive or negative according to whether the value of the baseline frontal QRS-T angle minus the post PCI frontal QRS-T angle is positive or negative. A total of 314 consecutive patients with ACS who underwent PCI were divided into two groups based on their negative frontal QRS-T angle change (n = 152 patients) and positive frontal QRS-T angle change (n = 162 patients). Results: Multivariate logistic regression analysis showed that the C-reactive protein (CRP) to albumin ratio (CAR) (Odds ratio [OR]: 0.519, 95% CI: 0.373–0.724, p <0.001), total bilirubin (OR: 3.687, 95% CI: 1.151–8.095, p = 0.03), and low-density lipoprotein (LDL) (OR: 0.985, 95% CI: 0.970–1.000, p = 0.04) were independent predictors of positive QRS-T angle change. In receiver operating characteristics curve analysis, a cut-off value of 0.59 total bilirubin had a 69% sensitivity and a 65% specificity (area under curve: 0.739, p <0.001) for the prediction of positive QRS-T angle change. Conclusion: In ACS patients, serum total bilirubin has been found to be a useful decision-making tool to predict positive frontal QRS-T angle change as a sign of reduced total ischemic burden, to assess early invasive strategy independently from other study parameters.