Aims: Nurse-led case management (CM) may improve quality of life (QoL) for advanced heart failure (HF) patients. No systematic review (SR), however, has summarized its effectiveness/cost-effectiveness. We aimed to evaluate the effect of such programs in primary care settings in advanced HF patients. We examined and summarized evidence on QoL, mortality, hospitalization, self-care, and cost-effectiveness. Methods and results: The MEDLINE, CINAHL, Embase, Clinical Trials, WHO, Registry of International Clinical Trials, and Central Cochrane were searched up to March 2022. The Consensus Health Economic Criteria instrument to assess risk-of-bias in economic evaluations, Cochrane risk-of-bias 2 for clinical trials, and an adaptation of Robins-I for quasi-experimental and cohort studies were employed. Results from nurse-led CM programs did not reduce mortality (RR 0.78, 95% CI 0.53 to 1.15; participants = 1345; studies = 6; I = 47%). They decreased HF hospitalizations (HR 0.79, 95% CI 0.68 to 0.91; participants = 1989; studies = 8; I = 0%) and all-cause ones (HR 0.73, 95% CI 0.60 to 0.89; participants = 1012; studies = 5; I = 36%). QoL improved in medium-term follow-up (SMD 0.18, 95% CI 0.05 to 0.32; participants = 1228; studies = 8; I = 28%), and self-care was not statistically significant improved (SMD 0.66, 95% CI −0.84 to 2.17; participants = 450; studies = 3; I = 97%). A wide variety of costs ranging from USD 4975 to EUR 27,538 was observed. The intervention was cost-effective at ≤EUR 60,000/QALY. Conclusions: Nurse-led CM reduces all-cause hospital admissions and HF hospitalizations but not all-cause mortality. QoL improved at medium-term follow-up. Such programs could be cost-effective in high-income countries.