Background: Implementing high reliability organization principles can enhance quality and safety in healthcare. Evidence-based instructions on how to effectively change the organizational culture in healthcare setting are required. Objectives: A systematic review investigating methods, facilitators, and barriers to assist healthcare organizations in becoming a high reliability organization. Method: Literature searches were performed in PubMed, MEDLINE, CINAHL-Complete, EMBASE, and Scopus for articles published between January 2012 and October 2017. The included articles were case reports, case studies, and protocol development studies on implementing high reliability organization principles. The articles were appraised using a modified Critical Appraisal Skills Programme tool. Thematic synthesis was conducted using manual coding. Results: Of the 14 eligible articles nine were case studies, four were case reports, and one was a framework development report. The study populations varied from whole healthcare systems to a single department of a hospital. The most common methods were supportive leadership, staff education, and analysing the safety events and sharing the knowledge. Cost was one of the barriers. Remuneration came in reduction of safety events and costs avoided. Conclusion: Implementing high reliability organization principles in healthcare settings is slow and challenging, but doing so improves quality, resilience, and safety, thus increasing productivity.