Background: Telehealth technologies can enhance patients' and their families' access to high-quality resources in home-based palliative care. Nurses are deeply involved in delivering telehealth in home-based palliative care. However, no previous integrative systematic reviews have synthesized evidence on nurses' roles, facilitators, and barriers to implementing nurse-delivered telehealth in home-based palliative care. Objective: This integrative systematic review aimed to provide a comprehensive understanding of the roles of nurses and the multilevel facilitators and barriers to implementing nurse-delivered telehealth in home-based palliative care, which could inform future policy development, research, and clinical practice. Methods: This integrative systematic review was conducted using Joanna Briggs Institute methodological guidance. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We systematically searched articles published from January 1, 2014, to May 2024 in PubMed, Embase, Web of Science, CINAHL, and Cochrane Library. We included English-language; peer-reviewed; original; and qualitative, quantitative, and mixed methods studies that centered on nurse-delivered telehealth in home-based palliative care. We used the Mixed Methods Appraisal Tool to assess the quality of the included articles. Furthermore, 3 authors independently assessed eligibility, extracted data, and assessed the quality of articles. The entities to extract were identified by research questions of interest regardless of the type of study. We applied a convergent synthesis approach to integrate quantitative and qualitative data. Guided by the updated Consolidated Framework for Implementation Research (CFIR) 2.0, we synthesized the facilitators and barriers to implementing nurse-delivered telehealth in home-based palliative care. Results: This integrative systematic review identified 4819 unique articles, including 34 papers encompassing 29 unique primary research studies. Innovations were mainly delivered by nurses (n=8) and nurse-involved multiprofessional teams (n=18). The roles of nurses in telehealth home-based palliative care involve palliative care nurses, community nurses, nurse coordinators, nurse coaches or nurse navigators, and nurse case managers. Guided by CFIR 2.0, facilitators and barriers to implementing nurse-delivered, telehealth, home-based palliative care were identified to 6 implementation levels and 20 constructs. The key facilitators included the COVID-19 pandemic, cost avoidance to the health care system, engagement of patients and their family caregivers, and so on. The barriers included a lack of reimbursement and payment mechanisms, technical problems, insufficiently trained health care providers, and so on. Conclusions: This integrative systematic review synthesizes evidence on nurses' evolving roles in telehealth home-based palliative care and identifies multilevel facilitators and barriers to nurse-delivered, home-based palliative care implementation. With the empowerment of telehealth technologies, nurses could establish a stronger professional identity and develop leadership in home-based palliative care. Nurses should leverage influence to promote nursing practice, clinical management, and policy support in the implementation of telehealth home-based palliative care. Trial registration: PROSPERO CRD42024541038; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024541038.