BACKGROUND: Cardiac resynchronization therapy (CRT) response in heart failure (HF) patients is multifactorial, with limited data on its association with activities of daily living assessed by the Barthel index (BI). OBJECTIVE: This prospective observational study investigated the predictive value of BI for CRT response and long-term clinical outcomes in non-ischemic HF patients with left bundle branch block (LBBB). METHODS: A total of 271 consecutive non-ischemic HF patients undergoing CRT with left ventricular ejection fraction (LVEF) ≤ 35% and LBBB were enrolled. BI was evaluated pre-implantation. The primary endpoint was CRT response (absolute LVEF improvement ≥ 5% at 6 months). The secondary composite endpoint included all-cause mortality and HF hospitalization (HFH). RESULTS: Among 249 patients completing 6-month follow-up, the CRT response rate was 68.67%. Multivariate logistic regression identified BI (per 5-point increment; OR = 1.37, 95% CI:1.12-1.67, p = 0.002) as an independent predictor of CRT response, with an optimal cutoff of 95. Combining BI with left ventricular end-diastolic diameter and left bundle branch area pacing achieved the highest predictive efficacy (AUC = 0.78). Over a median 33.94-month follow-up, BI > 95 was associated with an 88% reduced risk of the composite endpoint (adjusted HR = 0.116, p < 0.001), driven primarily by marked HFH reduction. A non-significant trend toward lower all-cause mortality was observed, accompanied by sustained LVEF improvement (29.81% ± 5.01% to 51.71% ± 11.30%). CONCLUSION: BI might be a simple, cost-effective independent predictor for CRT response and improved LVEF and prognosis in non-ischemic HF patients with LBBB.