Background and aims: The COVID-19 pandemic poses a grim challenge to adolescents' daily life, including schooling and learning, which has great impacts on their mental and behavioral health. This study aimed to test the roles of stress related to schooling and online learning during COVID-19 (COVID-19 stress) in depression and Internet gaming disorder (IGD) among adolescents and the potential mediators of social support, academic stress, and maladaptive emotion regulation based on the framework of Conservation of Resources theory. Sex differences in these associations were further examined. Methods: A school-based survey was conducted among Chinese adolescents in 13 secondary schools in Hong Kong (n = 3,136) from September to November 2020 (48.1% males; mean age = 13.6 years old) using stratified random sampling. Results: The prevalence of probable depression and IGD was 60% and 15%, respectively. Results of structural equation modeling indicated that the proposed model fit the data well (Χ²/df = 7.77, CFI = 0.92, IFI = 0.92, RMSEA = 0.05). COVID-19 stress was positively and indirectly associated with both depression and IGD through social support, academic stress, and maladaptive emotion regulation. Multi-group analyses identified that the associations between COVID-19 stress and academic stress, between academic stress and depression, and between social support and depression were stronger among females compared to males. Discussion and conclusions: Findings highlight the roles of academic stress, poor social support, maladaptive emotion regulation, and sex to understand how disruption and stress caused by COVID-19 increases adolescent depression and IGD. Psychosocial interventions based on these factors are highly warranted. Copyright © 2021 Akademiai Kiado.