Background Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by progressive ventricular dilation and systolic dysfunction despite optimized therapy. Identifying reliable markers that predict outcomes and monitor disease evolution remains a clinical challenge. This study investigated the prognostic significance of serial N-terminal pro–B-type natriuretic peptide (NT-proBNP) changes in relation to echocardiographic remodeling parameters among patients with NIDCM. Methods In a prospective cohort of 156 patients with NIDCM, serial NT-proBNP measurements and transthoracic echocardiography were performed at baseline, 12 months, and 24 months. Patients were categorized according to NT-proBNP trajectory: Responders (≥30% reduction), Stable (<30% change), and non-responders (≥30% increase). Echocardiographic indices included left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and left atrial volume index (LAVI). The composite endpoint was all-cause mortality or heart failure (HF) hospitalization. Kaplan–Meier analysis, multivariable Cox regression, and receiver operating characteristic (ROC) analyses were used to evaluate predictive value. Results At 24 months, 38% of patients were classified as responders, 34% as stable, and 28% as non-responders. Responders exhibited significant improvement in LVEF (from 33.2 ± 6.7% to 44.5 ± 8.2%, p < 0.001) and GLS (from −9.3 ± 2.5% to −12.7 ± 3.1%, p < 0.001), accompanied by reductions in LAVI and pulmonary pressures. A ≥30% NT-proBNP decline independently predicted reduced risk of the composite endpoint (HR 0.41; 95% CI 0.25–0.69; p < 0.001). The integrated NT-proBNP + echocardiographic model achieved superior discrimination compared with NT-proBNP alone (AUC 0.86 vs 0.74, p = 0.004). Conclusions Dynamic reductions in NT-proBNP are closely associated with echocardiographic evidence of reverse remodeling and improved clinical outcomes in NIDCM. The combination of serial biomarker assessment and imaging parameters enhances risk stratification beyond either modality alone. This multimodal approach may facilitate personalized, response-guided management in chronic non-ischemic cardiomyopathy.