Background <p>Adolescents are spending more time on screens, which has been associated with anxiety, depression, and increased substance use, especially through social media. This study aimed to examine the prospective relationship between screen time and anxiety/depression and the moderating effect of alcohol/e-cigarette use.</p> Methods <p>Data were drawn from the Adolescent Brain and Cognitive Development (ABCD) study, with participants aged 9–10 at baseline (<i>n</i> = 9,474). This cohort study analyzed longitudinal data collected between 2016 and 2022. Parents completed the Child Behavior Checklist (CBCL), which assessed anxiety/depression at the year 3 follow-up. Group-based trajectory models identified screen time/social media patterns, and multivariable linear models examined anxiety/depression, including an interaction term for alcohol/e-cigarette use.</p> Results <p>Four groups of screen time were identified. Higher screen time groups showed higher anxiety and depression (<i>p</i> ≤ 0.001) compared to the persistent low screen time group. Five groups of social media use were identified. The gradual increase to moderate time on social media group showed lower anxiety (<i>p</i> = 0.031) but similar depression t-scores compared to the largest group with persistent low use of social media. In contrast, the other three groups with high time spent on social media by the end of the study had similar anxiety but higher depression t-scores relative to the largest group (<i>p</i> ≤ 0.014). Alcohol/e-cigarette use did not moderate these relationships.</p> Discussion <p>Higher screen time was associated with higher anxiety and depression, while moderate social media use was associated with lower anxiety. High social media use was associated with higher depression. These findings highlight nuanced mental health impacts of screen behaviors as well as the need for public health strategies that emphasize moderation and promote balanced screen behaviors.</p>