Blood biomarkers to predict cancer therapy-related cardiac dysfunction (CTRCD) risk remain limited. The aim of this study was to identify circulating biomarkers associated with CTRCD risk in HER2⁺ breast cancer patients. In the discovery cohort, women with early-stage HER2⁺ breast cancer receiving anthracycline and trastuzumab therapy underwent serial evaluation with cardiac magnetic resonance imaging (CMR), echocardiography, clinical assessments, and blood biobanking every 3 months. Multiomics profiling of 3 circulating cardiac damage biomarkers and 35 markers of inflammation, angiogenesis and endothelial activation and profiling of >2,000 plasma microRNAs were performed before and early during treatment (3 and 6 months). CTRCD was defined by left ventricular ejection fraction measured on CMR, and sensitivity analyses used echocardiography. Pretreatment protein biomarkers were measured in a validation cohort. Among 136 women, 37 (27.2%) developed CMR-defined CTRCD within 15 months. The endothelial activation markers angiopoietin-2, endothelin-1, and endoglin were elevated before and during treatment, while sE-selectin was elevated during treatment in patients who developed CTRCD. Inflammatory biomarkers (myeloperoxidase, interferon-gamma-induced protein-10, and interferon-α) were significantly higher before treatment in patients who developed CTRCD. No differences were observed in cardiac injury biomarkers (troponin I, B-type natriuretic peptide, and growth differentiation factor-15). Pretreatment plasma microRNAs revealed distinct CTRCD-associated signatures. Integrating pretreatment clinical variables, CMR parameters, and biomarkers into a single random forest model, angiopoietin-2, myeloperoxidase, and endoglin were identified as the strongest predictors of CTRCD, findings that were subsequently validated in a cohort of 38 HER2⁺ breast cancer patients. Pretreatment endothelial-centric and inflammatory biomarkers outperformed both clinical and CMR measures in predicting CTRCD during chemotherapy.