Background: Adolescence is a critical developmental stage for the emergence of major depressive disorder (MDD). Structural and diffusion neuroimaging studies have highlighted the anterior cingulate cortex (ACC) as a key region implicated in emotion regulation, stress reactivity, and mood processing. However, few studies have examined whether microstructural characteristics of the ACC, reflected by mean diffusivity (MD) within gray matter–white matter (GM–WM) contrast regions, are associated with depression in early adolescence. Objective: To examine whether mean diffusivity (MD) within the GM–WM contrast of the left caudal anterior cingulate cortex (ACC) is associated with a past diagnosis of MDD among adolescents in the Adolescent Brain Cognitive Development (ABCD) Study, after accounting for demographic, socioeconomic, and adversity-related factors. Methods: Data were drawn from adolescents with diffusion MRI–derived mean diffusivity measures and diagnostics. The independent variable was mean diffusivity (MD) of the GM–WM contrast in the left caudal ACC. The primary outcome was past MDD diagnosis based on structured psychiatric assessments. Covariates included age, sex, socioeconomic status (SES), and exposure to adverse childhood experiences (ACEs). Logistic regression models tested the association between ACC MD and past MDD. A secondary model evaluated the relationship between ACC MD and past suicide attempt. Results: Mean diffusivity of the left caudal ACC was associated with the odds of past MDD, independent of age, sex, SES, and adversity exposure. In contrast, ACC mean diffusivity was not associated with a history of suicide attempt. Conclusions: Increased mean diffusivity in the caudal ACC may indicate microstructural alterations associated with depressive vulnerability in adolescence. ACC tissue integrity may serve as a sensitive neural correlate of early-onset depression.