Abstract Background Suboptimal self-care is associated with adverse patient outcomes. Nurse-led self-care interventions, strategies used to support self-care, are essential to heart failure management. However, research evidence of the effects of nurse-led heart failure self-care interventions on patient outcomes (quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality) is scant. Purpose To evaluate the effects of nurse-led self-care interventions on quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality in people with heart failure. Methods Six databases (MEDLINE, Embase, Web of Science, CENTRAL, CINAHL, and PsycINFO) were searched from the inception to December 2022 to identify eligible studies. Randomized controlled trials estimating the effectiveness of nurse-led self-care interventions on quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality in people with heart failure published in English were included. The risk of bias of included studies was assessed using RoB 2.0. We conducted data syntheses by means of R software and graded the quality of the evidence using the GRADE approach. Results Twenty-five studies with 2746 subjects were included. Our findings demonstrated that compared to the controls, nurse-led self-care interventions improved quality of life (standardized mean difference [SMD]: 0.83, 95% confidence interval [CI]: 0.50 to 1.15, moderate certainty of evidence), anxiety (mean difference [MD]: 1.83, 95% CI: 1.10 to 2.56, high certainty of evidence), and symptom burden (SMD: 0.81, 95% CI: 0.24 to 1.38, low certainty of evidence) in people with heart failure. No significant effects were found in all-cause hospital readmission and all-cause emergency department visit. Research evidence on sleep quality, cardiac-related hospital readmission, cardiac-related emergency department visit, and all-cause mortality remained unclear. Conclusions Our review suggests that nurse-led heart failure self-care interventions have favorable effects on the quality of life, anxiety, and symptom burden. Further well-designed randomized controlled trials are warranted to address the gaps identified in this review.