The Physical Activity Guidelines Advisory Committee Scientific Report identified important research gaps to inform future guidance for adolescents, including limited evidence on the importance of sedentary behaviors (screen time) and their interactions with physical activity for adolescent health outcomes, including overweight and obesity. To identify the independent associations of physical activity and screen time categories, and the interactions between physical activity and screen time categories, with body mass index (BMI) and overweight and obesity in adolescents. This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) Study collected from September 10, 2018, to September 29, 2020. Data were analyzed from July 8 to December 20, 2022. A total of 5797 adolescents aged 10 to 14 years from 21 racially and ethnically diverse study sites across the US were included in the analysis. Categories of total step count per day (with 1000 to 6000 steps per day indicating low, >6000 to 12 000 steps per day indicating medium, and >12 000 steps per day indicating high), as measured by a wearable digital device (Fitbit), and categories of self-reported screen time hours per day (with 0 to 4 hours per day indicating low, >4 to 8 hours per day indicating medium, and >8 hours per day indicating high). Participant BMI was calculated as weight in kilograms divided by height in meters squared and converted into sex- and age-specific percentiles in accordance with the Centers for Disease Control and Prevention growth curves and definitions. Individuals were classified as having overweight or obesity if their BMI was in the 85th percentile or higher for sex and age. Among 5797 adolescents included in the analytic sample, 50.4% were male, 61.0% were White, 35.0% had overweight or obesity, and the mean (SD) age was 12.0 (0.6) years. Mean (SD) reported screen time use was 6.5 (5.4) hours per day, and mean (SD) overall step count was 9246.6 (3111.3) steps per day. In models including both screen time and step count, medium (risk ratio [RR], 1.24; 95% CI, 1.12-1.37) and high (RR, 1.29; 95% CI, 1.16-1.44) screen time categories were associated with higher overweight or obesity risk compared with the low screen time category. Medium (RR, 1.19; 95% CI, 1.06-1.35) and low (RR, 1.30; 95% CI, 1.11-1.51) step count categories were associated with higher overweight or obesity risk compared with the high step count category. Evidence of effect modification between screen time and step count was observed for BMI percentile. For instance, among adolescents with low screen use, medium step count was associated with a 1.55 higher BMI percentile, and low step count was associated with a 7.48 higher BMI percentile. However, among those with high screen use, step count categories did not significantly change the association with higher BMI percentile (low step count: 8.79 higher BMI percentile; medium step count: 8.76 higher BMI percentile; high step count: 8.26 higher BMI percentile). In this cross-sectional study, a combination of low screen time and high step count was associated with lower BMI percentile in adolescents. These results suggest that high step count may not offset higher overweight or obesity risk for adolescents with high screen time, and low screen time may not offset higher overweight or obesity risk for adolescents with low step count. These findings addressed several research gaps identified by the Physical Activity Guidelines Advisory Committee Scientific Report and may be used to inform future screen time and physical activity guidance for adolescents.