Previous research has linked an imbalance of the tissue inhibitors of metalloproteinase-1 (TIMP-1) and fibronectin (FN) to heart failure as a part of the extracellular matrix network (ECM) biochemistry profile, which is vital for cardiac homeostasis. This study aimed to assess the diagnostic performance of FN, TIMP-1, and CK-MB in heart failure (HF). Sixty patients (45 with acute and 15 with chronic HF) were recruited. Thirty individuals (20 with ischemic heart diseases, as other cardiac diseases, and 10 healthy individuals) were recruited as a control group. The biotin double antibody sandwich technology determined levels of human fibronectin and tissue inhibitors of metalloproteinase-1. FN was the most effective biomarker in differentiating HF patients from healthy individuals (AUC = 0.850) (P < 0.001), followed by TIMP (AUC = 0.74) and CK MB (AUC = 0.660). The sensitivity and specificity of FN were 82% and 70%, respectively, at a cutoff of 80 ng/ml. In addition, FN and TIMP had the same AUC (0.71) and efficiency (65%) in distinguishing HF patients from controls, followed by CK-MB (AUC = 0.70). We developed a novel model for HF diagnosis named the HFD model based on three biomarkers (FN, TIMP, and CK MB). The HFD model had an AUC of 0.77 in distinguishing HF patients from healthy individuals, with a sensitivity, specificity, and accuracy reaching 80%. For differentiating HF patients from controls, the HFD model had 0.8 AUC, 76% sensitivity, 75% specificity, and 76% accuracy.