Social prescribing is a growing health policy agenda to improve the quality and effectiveness of health systems. However, systematically collected knowledge on factors influencing the effective implementation of SP is scarce. A systematic review was conducted to identify and categorize factors influencing social prescribing initiatives. A search of three electronic databases (PubMed, Scopus, and ISI Web of Knowledge) was carried out to retrieve studies from inception to May 2022, supplemented by grey literature searching and snowballing of the relevant references. The inclusion criteria were original empirical research, qualitative data collection, and a description of factors affecting social prescribing initiatives. Study quality was evaluated using the Critical Appraisal Skills Programme tool. We categorized the results of individual studies using a narrative approach. A total of 23 studies were included for analysis. Along with patient-related factors (patient-centeredness, clinical complexity, perception, knowledge), three main settings of social prescribing initiatives (including healthcare providers, link workers, and voluntary and community sectors) are affected by (1) individual characteristics (knowledge, perception, skill mix); (2) interpersonal relations (collaboration, trust, feedback, supportive climate, follow-up, sustained connection, peer support within and across sectors); (3) organizational contingencies (resource adequacy, staffing, training, role description, continuity of support, caseload management, monitoring, affordability, accessibility, referral criteria, and tailored support); and (4) political context (national policy and guidance, stewardship, planning, cocreation, bureaucracy, economic condition, and the number of support organizations). Many factors influencing social prescribing initiatives were identified. The results of this review can be applied by different stakeholders of social prescribing to guide development, implementation, description, and evaluation.