Background: Medical students often experience self-doubt due to the demanding nature of their coursework and numerous assignments, which may indicate Imposter Syndrome (IS). Objectives: This study aimed to evaluate the effectiveness of cognitive behavioral therapy (CBT) in improving mental health, self-esteem, and emotional regulation among medical students dealing with IS. Methods: A semi-experimental design was used, incorporating a pre-test-post-test approach with a control group. The statistical sample included medical students from Tarbiat Modares University in 2023. A total of 36 students were selected through purposeful sampling and randomly assigned to either the experimental group (n = 18) or the control group (n = 18). Data collection tools included questionnaires assessing IS, mental health, self-esteem, and emotion regulation. The experimental group received eight 90-minute CBT sessions based on the approach by Egan and Shafran (2017), while the control group received no intervention. Data were analyzed using a multivariate analysis of covariance with SPSS24 software. Results: The results showed that CBT significantly reduced expressive suppression (F = 78.04, η² = 0.72) and increased mental health (F = 37.73, η² = 0.56), self-esteem (F = 54.76, η² = 0.64), and cognitive reappraisal (F = 35.65, η² = 0.55) among students with IS (P < 0.001). Conclusions: The findings suggest that CBT is an effective intervention for improving the psychological well-being of medical students experiencing IS. The significant improvements in mental health, self-esteem, and emotional regulation underscore CBT's potential as a valuable tool for this population.