Introduction: cognitive flexibility and self-differentiation are the appropriate models for understanding psychological problems through which people can meet various challenges. The aim of this study was to investigate the relationship between cognitive flexibility and self-differentiation with psychological problems among female students in Allameh Tabataba’i University. Materials and Methods: The method of this study was descriptive-correlational and statistical population was comprised of all female students at AllamehTabataba’i University in Tehran who have been studying between 2014-2015. Using random multiple cluster sampling method, a group of 380 students were selected. Tools were questionnaires of cognitive flexibility, self-differentiation and symptoms checklist (SCL-90-R). Data were analyzed by descriptive statistical parameters, correlation coefficient, and regression analysis. Results: Analysis revealed a significant correlation between total score of psychological problems with cognitive flexibility and self-differentiation. In addition, the results of multiple regression analysis showed that cognitive flexibility and self-differentiation can explain different kinds and levels of psychological problems in students. Conclusion: study of cognitive flexibility and self-differentiation are efficient methods to understand the underlying factors associated with psychological problems. Evaluation of these factors can lead to a new approach in prevention and treatment of psychological problems.