Background: Vascular inflammation and vasculotoxic heavy metals have each been linked to acute coronary syndrome (ACS) but have rarely been studied together. This study compared serum pentraxin-3 (PTX-3), a proposed marker of local vascular inflammation, and whole-blood lead (Pb), arsenic (As), and nickel (Ni) between ACS patients and controls. Methods: In this single-center, cross-sectional case–control study, 50 patients with angiographically confirmed ACS were compared with 50 age- and sex-comparable emergency department controls with minor non-cardiac complaints. Results: PTX-3, Pb, As, and Ni were higher in ACS patients (all false discovery rate-adjusted q < 0.001). Between-group discrimination was highest for Pb (area under the curve [AUC] 0.962) and PTX-3 (AUC 0.951). PTX-3 and Pb remained independently associated with ACS after adjustment for hypertension, hyperlipidemia, and smoking and, separately, for age, diabetes, and renal function. Within the ACS group, PTX-3 was not significantly correlated with the Gensini score (ρ = 0.12, p = 0.41). Conclusions: PTX-3 and whole-blood Pb, As, and Ni were markedly elevated in ACS, with PTX-3 and Pb showing the strongest and most robust associations. Prospective multicenter studies in patients with suspected ACS are needed to confirm these findings and establish whether these biomarkers add value beyond established clinical assessment.