Recognition of the factors affecting the medical students' academic success is one of the most important challenges and concerns in medical schools. Hence, this study aimed to investigate the mediating effects of metacognitive learning strategies and learning-related emotions in the relationship between academic self-efficacy with academic performance in medical students. Methods: The present study was carried out on 279 students of medicine studying at Shiraz University of Medical Sciences. The students filled out three questionnaires: academic emotions (AEQ), metacognitive learning strategies, and academic self-efficacy questionnaires. The data were analyzed using SPSS and Smart PLS3. Results: The results of structural equation modeling revealed that the students' self-efficacy has an impact on their learning-related emotions and metacognitive learning strategies, and these, in turn, affect the students' academic performance. Moreover, learning-related emotions influence the metacognitive learning strategies, which in turn mediate the effect of emotions on academic performance. Discussion: The results of this study revealed that metacognitive strategies and learning-related emotions could play a mediating role in the relationship between students' self-efficacy and academic performance.