Background <p>A variety of unhealthy lifestyle behaviors (ULBs) in adolescence often exist in the form of “clustering”, and anxiety and depression often appear as comorbidities. We aimed to explore the prospective relationship between the clustered unhealthy lifestyle behaviors and comorbidity of anxiety and depression in adolescents.</p> Methods <p>Data were collected from the Chinese Adolescent Health Surveillance and Cohort Study with a sample of 6 656 adolescents. LCA was used to identify clustering patterns of multiple unhealthy lifestyle behaviors. Anxiety and depression symptoms were evaluated by GAD-7 and PHQ-9. Multivariate logistic regression model was established to analyze the association between the clustering patterns and clustering quantity of unhealthy lifestyle behaviors and the comorbidity of anxiety and depression symptoms.</p> Results <p>Multivariate logistic regression results showed that the sedentary/screen-time group (<i>OR</i> = 1.51, 95%<i>CI</i>: 1.19–1.90) and the Multiple unhealthy behaviors group (<i>OR</i> = 3.65, 95%<i>CI</i>: 2.90–4.61) significantly increased the risk of comorbidity of anxiety and depression symptoms. 4–6 (<i>OR</i> = 1.42, 95%<i>CI</i>: 1.14–1.80) and ≥ 7 (<i>OR</i> = 2.76, 95%<i>CI</i>: 2.18–3.52) unhealthy lifestyle behaviors clustering quantity significantly increased the risk of comorbidity of anxiety and depression symptoms.</p> Conclusion <p>Clustered unhealthy lifestyle behaviors are common among adolescents and strongly associated with an increased risk of subsequent anxiety-depression comorbidity. These results emphasize the necessity of monitoring adolescents with high-risk behavioral profiles. Targeted lifestyle modifications may be effective strategies for the early prevention and intervention of comorbid mental health disorders in youth.</p> Clinical trial number <p>Not applicable. (This is a cohort observational study and does not involve a clinical trial requiring prospective registration.)</p>