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The long-term mental health consequences of COVID-19 in children and adolescents remain unclear. We investigated the impact of COVID-19 infection on mental health after China's zero-COVID policy relaxation, focusing on symptom-specific and social-family risk factors for mental health issues in children and adolescents. In a longitudinal study, 8348 youths (aged 10-18) were assessed twice (T1: September to October 2022 and T2: April to May 2023). Mental health changes (Δ=T1-T2) were compared between COVID-19-infected (COVID+, n = 4108) and non-infected (COVID-, n = 4240). After balancing social-family confounding factors at T1 with propensity score-based inverse probability weights, multivariable logistic regression was employed to assess associations between COVID-19 infection and the onset/worsening of mental health symptoms. Multivariable logistic regression was conducted to explore specific acute COVID-19 symptoms and social-family risk factors associated with the onset/worsening of mental health symptoms in COVID + group. Compared to COVID- group, COVID + group exhibited lower overall mental health improvement (Δ). COVID + group was associated with increased risks of depression worsening (OR 1.20, 95 % CI 1.04-1.39), anxiety worsening (OR 1.30, 95 % CI 1.15-1.47), stress worsening (OR 1.23, 95 % CI 1.03-1.46), insomnia worsening (OR 1.21, 95 % CI 1.05-1.39), and emotional symptoms worsening (OR 1.72, 95 % CI 1.27-2.33). Moderate-to-severe difficulty thinking, breathlessness, and gastrointestinal symptoms were specific COVID-19 symptoms associated with worsening of various mental health outcomes. Furthermore, academic difficulties, economic disadvantages, family conflicts, food addiction, and alcohol consumption were identified as social-family risk factors for worsening mental health symptoms in COVID + youths. COVID-19 infection leaves lasting mental health scars in youths, extending beyond the acute phase. Specific symptoms, particularly cognitive dysfunction and respiratory/gastrointestinal distress play a significant role in this vulnerability. Social-family factors further modulate these effects, highlighting the need for comprehensive interventions that address both biological and psychosocial aspects. This study provides valuable insights for tailoring mental health support to youths navigating the consequences of the COVID-19 pandemic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)