Background Blended learning means using more than one method, strategy, technique, and medium in education to provide content and training materials. This method can affect student’s learning owing to its flexibility and ability to use advantages of both face to face and e-learning methods. The aim of this study was to compare the effects of two methods of blended and face to face learning on the knowledge and performance of master’s degree students of Shiraz University of Medical Sciences. Methods This research is a quasi-experimental study designed as pretest/posttest, which was conducted on 60 students. Based on the criteria, the selected students were randomly divided into two groups of 30 individuals to receive either blended or face to face learning. Data were collected at pretest and posttest using questionnaires and checklists. The acceptable significance level was set at 0.05 (α = 0.05). Face and content validity of the questionnaire and checklist were assessed by four professors in the field of education. Reliability of the questionnaire and checklist was assessed using Cronbach’s alpha, which gave the values of 0.72 and 0.7, respectively. Data were analyzed through paired and independent t-tests in SPSS version 19. Results Results showed that the increases in pretest scores compared to posttest scores were significantly higher in the blended learning group than the face-to-face learning group (P < 0.05). The score of the blended learning group also showed a significant increase compared to the other group (P < 0.05). Conclusions If the methods, techniques, and educational media are used in the right place (according to the target group) and the right way, it can help improve and facilitate learning.