Background: The European Society of Cardiology guidelines recommend the implementation of nurse-led heart failure programs to achieve optimal management of patients with congestive heart failure (CHF). In this analysis, we aimed to systematically show the impact of nurse-led interventions (NLI) on re-admission and mortality in patients with CHF (reduced ejection fraction). Methods: Publications reporting the impact of NLI on readmission and mortality in patients with CHF were carefully searched from electronic databases. Rehospitalization and mortality were the endpoints. For this analysis, the latest version of the RevMan software was used. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data following analysis. Results: A total number of 3282 participants with CHF were included in this analysis. A total of 1571 patients were assigned to the nurse-led intervention group whereas 1711 patients were assigned to the usual care group. The patients had a mean age ranging from 50.8 to 80.3 years. Male patients varied from 27.3% to 73.8%. Comorbidities including hypertension (24.6%–80.0%) and diabetes mellitus (16.7%–59.7%) were also reported. Patients had a mean left ventricular ejection fraction varying from 29.0% to 61.0%. Results of this current analysis showed that rehospitalization (RR: 0.81, 95% CI: 0.74–0.88; P = .00001) and mortality (RR: 0.69, 95% CI: 0.56–0.86; P = .0009) were significantly lower among CHF patients who were assigned to the nurse-led intervention. Whether during a shorter (3–6 months) or a longer (1–2 years) follow up time period, rehospitalization for shorter [(RR: 0.73, 95% CI: 0.65–0.82; P = .00001) vs for longer (RR: 0.81, 95% CI: 0.72–0.91; P = .0003) respectively] and mortality for shorter [(RR: 0.55, 95% CI: 0.38–0.80; P = .002) vs longer follow up time period (RR: 0.76, 95% CI: 0.58–0.99; P = .04) respectively] were significantly lower and in favor of the nurse-led interventional compared to the normal care group. Conclusions: This systematic review and meta-analysis of randomized controlled trials showed that NLI had significant impacts in reducing the risk of rehospitalization and mortality in these patients with CHF (reduced ejection fraction). Hence, we believe that nurse-led clinics and other interventional programs would be beneficial to patients with heart failure and this practice should, in the future be implemented to the health care system.