Patient safety is the first and foremost goal, as well as it is a critical issue in the healthcare sector. To ensure achieving this goal, there is a continuous need for quality improvement. Six Sigma is known as one of the most effective improvement technologies widely adopted in healthcare systems that aims to reduce the variation and eliminate the defects. In this study, a systematic review of the literature is carried out to investigate the outcomes of implementing a Six Sigma tool in patient safety applications. The findings proved that applying Six Sigma in healthcare is valuable and useful in solving many raised issues, reduce medication errors, and increase patient safety. This paper provides opportunities, challenges, and techniques to investigate the relationship between Six Sigma and patient safety.  The paper presents valuable outcomes for healthcare quality and process improvement managers.