Introduction: Self-directed learning is one of the issues that play an important role in students' academic performance. Therefore, the present study aimed to investigate the effect of brain quadrants dominance on academic performance with the mediating role of self-directed learning of the students of Zahedan University of Medical Sciences. Method: This is a descriptive-correlational study with Structural Equation Modeling approach. The statistical population consisted of 5120 students of Zahedan University of Medical Sciences. Based on Karajsi and Morgan table, 357 individuals were selected by simple random sampling method. Herrmann Brain Dominance Instrument Questionnaire (1980), Fam and Taylor's Students' academic performance Questionnaire (2004) and Williams Self-directed learning Questionnaire (2004) were used for data collection. To measure validity of the questionnaire, content validity index& Ratio (CVI, CVR) was used. Based on Cronbach's alpha coefficient, the reliability of the questionnaires was estimated to be 0. 91, 0. 73 and 0. 94, respectively. Data analysis was performed by Pearson correlation test and Structural Equation Modeling via SPSS and LISREL. Results: Results show that the four-quadrant brain dominance had a direct effect on academic performance (B=0. 73, t=9. 25). The dominance had a direct effect on selfdirected learning (SDL) (B=0. 66, t=8. 31), and both direct (B=0. 439, t=8. 94) and indirect (B=0. 39) effects on the academic performance with a mediating role of selfdirected learning. Since it affected the academic performance through self-directed learning, therefore the mediating role of the variable in the four-quadrant brain dominance on academic performance was confirmed. The findings also indicated that the proposed model had a good fit (GFI=0. 95, RAMSEA=0. 07). Conclusion: Based on findings, the four-quadrant brain dominance had direct and indirect effects on the students' academic performance. Furthermore, the mediating role of self-directed learning on the students' academic performance was confirmed. Since the students' academic performance changed under the influence of education So, It is Suggested conduct programs to familiarize students with the brain quadrants, functions of brain quadrants, and the context of self-directed learning at the university.