BACKGROUND: Burnout and depression among medical students is linked to serious problems that require appropriate solutions. Subthreshold autism traits or autistic-like traits (ALTs) may be possible factors associated with burnout and depression. The effectiveness of acceptance and commitment therapy (ACT) for burnout and depression has been widely reported. The treatment aims to improve psychological flexibility, a concept indicating engagement in personal value-based behaviors without avoiding uncomfortable private experiences. This study examined whether ALTs were associated with burnout or depression among medical students during clinical clerkships in Japan, and then investigated what psychological flexibility processes might mediate these associations. METHODS: A cross-sectional survey was administered to 284 medical students at Nagoya City University School of Medical Sciences who had been in clinical clerkships for 10 months or longer. Linear multiple regressions were performed with each burnout factor or depression as the outcome variable using validated tools measuring burnout (Maslach Burnout Inventory), anxiety and depression (Hospital Anxiety and Depression Scale), ALT (Autism-Spectrum Quotient Japanese version-21), and psychological flexibility processes (Cognitive Fusion Questionnaire-7 and Valuing Questionnaire). Additionally, a mediation analysis was conducted using structural equation modeling. RESULTS: A linear multiple regression analysis that controlled for age and gender found that ALTs were significantly associated with lower personal accomplishment, a factor of burnout, and depression. Lower personal accomplishment was also associated with males and lower progress toward values of the psychological flexibility process. Depression was also associated with males and higher cognitive fusion, lower progress towards values, and higher obstruction to values of the psychological flexibility process. Surprisingly, emotional exhaustion and depersonalization were not significantly associated with ALTs. The mediation analysis revealed that the relationship between ALTs and personal accomplishment was partially mediated by a process of progress toward values, while the relationship between ALTs and depression was partially mediated by both processes of progress toward values and cognitive fusion. CONCLUSIONS: ALTs were significantly associated with lower personal accomplishment of burnout and depression among medical students in clinical clerkships. Consideration should be given to the psychological flexibility processes that focus on interventions targeting psychological flexibility for medical students with ALTs to reduce burnout and depression.