Background: Self-handicapping behaviors, characterized by creating obstacles or excuses to avoid failure, can hinder academic success. Understanding how academic motivation mediates the relationship between self-handicapping behaviors and academic performance is crucial for supporting medical students. Objectives: This study aimed to investigate the relationships between academic self-regulation, goal orientation, passion, and self-handicapping behaviors among medical students, with academic motivation as a potential mediator. Methods: The present study employed a descriptive, correlational approach to examine the relationships between variables within a structural equation modeling (SEM) framework. The population consisted of all undergraduate medical students with self-handicapping behaviors at Jundishapur University of Medical Sciences in 2022. The sample comprised 204 medical students selected using purposive sampling, who completed the Academic Passion Scale, Goal Orientation Scale, Academic Self-Regulation Scale, and Academic Motivation Scale. Structural equation modeling was used to analyze the model with AMOS 24. Results: The SEM analysis revealed that the proposed model had a good fit to the data (CFI = 0.96, RMSEA = 0.05). The results further demonstrated that goal orientation directly enhanced students' academic passion, while academic self-regulation did not have a direct impact. However, strong self-regulation indirectly increased passion by fostering academic motivation (P < 0.001). Similarly, goal orientation also worked indirectly through motivation to enhance academic passion (P < 0.05). Conclusions: This study underscores the importance of goal setting and academic motivation in fostering academic passion among medical students with self-handicapping behaviors. While academic self-regulation strategies may not directly translate to academic passion, they can contribute indirectly by fostering academic motivation. Educators and practitioners can promote academic passion and address self-handicapping behaviors in medical students by encouraging goal orientation, academic motivation, self-regulation, and providing support for overcoming challenges.