Background: The identification of the factors influencing the academic progress and performance of students can be a suitable basis for planning and developing educational programs to achieve the best possible results in line with educational development. Objectives: The present study aimed to investigate the mediating role of stress in the relationship of mindfulness and self-construal with the academic performance of medical sciences students. Methods: This was a descriptive correlational study in which the convenience sampling method was used to select 301 medical students from Jondishapur University of Ahvaz, Iran, in 2022. The participants completed the mindfulness, self-construal, and stress questionnaires. In addition, academic performance was measured based on the grade point average (GPA) in the previous semester. Structural equation modeling (SEM) and bootstrapping were also employed to examine the fit of the proposed model and indirect relationships between the variables, respectively. Results: The mean of academic performance, mindfulness, self-construal, and stress were obtained as 16.57, 57.6, 140.53, and 29.72, respectively. The results showed a significant relationship between all research variables (P < 0.05) except for the relationship between mindfulness and academic performance. The results also indicated that stress was a mediator in the indirect relationship of mindfulness and self-construal with academic performance (P < 0.001). The fit indices of the Tucker–Lewis index (TLI), comparative fit index (CFI), relative fit index (RFI), normed fit index (NFI), and Root Mean Square Error of Approximation (RMSEA) in the final model were 0.94, 0.96, 0.92, 0.94, and 0.077, respectively. Conclusions: The results confirmed the proposed model’s goodness of fit. Therefore, this model can be used for identifying the factors affecting the academic performance of medical students and developing programs to prevent academic failure and stress among these students.