Background: Dynamin-related protein 1 (Drp1) has been demonstrated as a crucial role in mediating the programed cell death and cardiac metabolism through its regulatory of mitophagy in animal studies. However, the clinical values of Drp1 for human cardiac disease remain unknown. This study is aimed to evaluate the diagnostic and prognostic values of serum Drp1 in these patients with heart failure (HF). Methods: The enzyme linked immunosorbent assay (ELISA) was used for measuring serum Drp1 concentrations in 85 cases of HF with preserved ejection fraction (HFpEF) and 86 cases of HF with reduced ejection fraction (HFrEF). The diagnostic value of Drp1 was evaluated using the receiver operating characteristic (ROC) analysis. The composite endpoint was consisted of cardiac death and rehospitalization for HF, and the association between Drp1 and clinical outcomes were further determined. Results: Serum Drp1 concentrations were much higher in HFpEF than that in HFrEF (4.2 \pm 3.7 ng/mL vs. 2.6 \pm 2.2 ng/mL, p = 0.001) and the ROC analysis demonstrated it as a potential diagnostic biomarker for distinction of the HF phenotypes, with an optimal cutoff point of 3.5 ng/mL (area under the curve (AUC) = 0.659, sensitivity: 45.9%, specificity: 83.7%). Kaplan-Meier survival analysis indicated that a low serum concentration of Drp1 (cut-off value = 2.5 ng/mL, AUC = 0.738) was in relation to poor prognosis of HF. Moreover, binary logistic regression analysis identified the low serum concentration of Drp1 as an independent risk predictor for rehospitalization (odds ratio (OR) = 6.574, p = 0.001) and a composite endpoint (OR = 5.927, p = 0.001). Conclusions: Our findings suggested that low serum concentrations of Drp1 might serve as a predicting biomarker for distinction of HF phenotypes and overall prognosis of HF.