Background and Objectives: Systemic inflammation is a key driver in the progression and complexity of coronary artery disease (CAD). Serum calprotectin and the C-reactive protein–triglyceride–glucose index (CTI) have emerged as potential inflammatory and metabolic biomarkers; however, their association with angiographic disease severity has not been clearly defined. This study aimed to evaluate the relationship between serum calprotectin, CTI, and the SYNTAX score (SS) in patients with stable CAD. Materials and Methods: A total of 134 patients undergoing coronary angiography were enrolled. The SS was calculated to quantify coronary lesion complexity. Patients were classified into two groups based on the results of the coronary angiogram: low SS (n = 73, SS <23), and intermediate–high SS (n = 61, SS >23). Serum calprotectin, and CTI were obtained at baseline. Correlation analyses were performed to evaluate associations between biomarkers and SS. Receiver operating characteristic (ROC) curve analysis assessed the ability of these biomarkers to predict intermediate–high SS. Univariable and multivariable logistic regression analyses were performed to determine independent associations. Results: Patients with intermediate–high SS had significantly higher levels of serum calprotectin (1009.5 vs. 505.7 ng/mL), and CTI (9.9 vs. 9.5) compared with those with low SS (all p<0.001). Spearman correlation analysis demonstrated significant positive correlations between SS and, serum calprotectin (ρ = 0.488), and CTI (ρ = 0.453) (all p < 0.001). ROC analysis showed moderate discriminatory performance for predicting intermediate–high SS (0.739 for serum calprotectin, and 0.722 for CTI). In multivariable models, CTI showed the strongest independent association with intermediate–high SS (OR: 4.66, 95% CI: 2.00–10.84, p<0.001). Conclusions: Serum calprotectin and CTI were significantly associated with coronary lesion complexity, as measured by the SS. These biomarkers may serve as valuable tools for identifying patients with greater CAD severity and anatomical complexity.