Heart failure with reduced ejection fraction (HFrEF) represents a significant public health burden associated with incremental health care costs. Given the limitations associated with pharmacological autonomic regulation therapy (ART), device-based autonomic neuromodulation is on the horizon now for ART in those patients. This systematic review aimed primarily to determine the effect of ART by devices on functional status and quality of life (QOL) in patients with HFrEF. We performed a meta-analysis of five randomized controlled trials (1074 patients) comparing ART by devices versus optimal medical therapy (OMT) in HFrEF. We assessed pooled estimates of odds ratio (OR) for improvement in New York Heart Association (NYHA) class and mean differences (MD) in 6-minute hall walk distance (6-MHWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro b-type natriuretic peptide (NT-proBNP) levels, and left ventricular end-systolic volume index (LVESVi) with their 95% confidence intervals (CIs) at 6-month follow-up. Compared to OMT alone, ART by devices in HFrEF significantly improves NYHA class (OR 2.26, 95% CI 1.33 to 3.83, P = 0.003), increases 6-MHWD (MD 45.53 m, 95% CI 30.61 to 60.45, P < 0.00001), improves MLHFQ score (MD − 10.59, 95% CI − 20.62 to − 0.57, P = 0.04) with neutral effect on NT-proBNP levels (MD − 236.5 pg/ml, 95% CI − 523.86 to 50.87, P = 0.11) and LVESVi (MD − 1.01 ml/m², 95% CI − 4.49 to 2.47, P = 0.57). We concluded that device-based neuromodulation therapy significantly improves functional status and quality of life in patients with HFrEF.