PURPOSE: Higher rates of depression are associated with autistic traits; however, the precise association between autistic traits and depression has yet to be fully elucidated. Good interpersonal emotional regulation and social self-efficacy are crucial for mental health; therefore, in this study, we investigated the relationships between autistic traits, interpersonal emotional regulation, social self-efficacy, and depression. PATIENTS AND METHODS: In total, 1024 participants (613 females and 411 males) aged 16 to 23 years old (M = 19.03, SD = 0.95) completed questionnaires that were designed to evaluate their autistic traits, interpersonal emotion regulation, social self-efficacy and depression. Data were analyzed by Spearman correlation and mediation effects analyses. RESULTS: Autistic traits were significantly and positively correlated with depression (r = 0.39, p < 0.001), and autistic traits were shown to positively predict depression (B = 0.28, p < 0.001). Interpersonal emotion regulation and social self-efficacy were found to play a serial mediating role between autistic traits and depression (indirect effect = 0.020, p = 0.006). CONCLUSION: This study is a supplement to the mechanism of the relationship between autistic traits and depression. Interpersonal emotion regulation and social self-efficacy are important predictors of possible depression in individuals with high autistic traits. These findings suggest combining interpersonal emotional regulation training and exploring the clinical value of interpersonal emotional regulation interventions in individuals with high autistic traits and autism spectrum disorder, aiming to build social confidence, reduce negative moods, restore social functioning, and other aspects.