Objective: To systematically synthesize research evidence on barriers and facilitators to pressure injury prevention in hospital settings. Methods: A systematic literature review of quantitative, qualitative, and mixed methods research was undertaken using PubMed, MEDLINE, Embase, CINAHL, and Cochrane Library. Studies that reported barriers or/and facilitators to pressure injury prevention in the acute care settings and published in English from 2008 to 2022 were included. Studies were excluded if they were conducted in residential care facilities and nursing homes, or other long-term community care settings. Two authors independently screened articles against the inclusion and exclusion criteria. Quality appraisal was conducted by two authors by using the Mixed Methods Appraisal Tool. Reported results were mapped to the Theoretical Domains Framework to identify the barriers and facilitators to pressure injury prevention. Results: A total of 78 studies were included. There were 65 quantitative studies, 11 qualitative studies, and two mix-methods studies. The most salient Theoretical Domains Framework domains identified in this review were “Knowledge”, “Skills”, “Environmental Context and Resources”, “Optimism”, “Social/Professional Role and Identity”, and “Social influences”. Conclusion: The barriers and facilitators to pressure injury prevention in hospital settings identified in this systematic review were diverse, and included issues at both individual and organizational level. Healthcare organizations can address the barriers and facilitators from the influential Theoretical Domains Framework domains. Future research is required to investigate the effectiveness of behaviour change interventions that specifically target these barriers and facilitators to pressure injury prevention.