Context Effective clinical skills training of medical students can guarantee a higher quality of care, diagnosis, and treatment for patients. Therefore, selection of appropriate methods of clinical education is of great significance. Mastery learning is one of the learning models in which educational progress is not dependent on time, but rather performance. In this model, the learner is constantly assessed until achieving mastery. All students can achieve the same level of learning, although the amount of time required for mastery is variable. Objectives The purpose of the present study was to review the literature on the effects of mastery learning on the clinical education of medical students. Data Sources This systematic review was conducted in English and Persian databases to evaluate articles on mastery learning in clinical education, published from 1990 to 2016. In the primary search, 503 articles were retrieved using Persian and English keywords, including “clinical teaching” and “mastery learning”. After reviewing the abstracts, 50 relevant articles were selected, and, finally, 26 articles were reviewed. Results Based on the findings, mastery learning can improve skill mastery among students, reduce the complications of medical interventions, increase the students’ self-confidence, reduce the required time for skill acquisition, increase the students’ knowledge, and improve their communication skills. Also, this method of learning has been effectively applied in medicine, nursing, and occupational therapy for students and hospital staff. Conclusions Mastery learning is a suitable method for teaching clinical skills to students. Considering the advantages of this method, it can be used effectively to train students from different medical disciplines.