BACKGROUND: The COVID-19 pandemic has disrupted the lives of children and adolescents worldwide. The German COPSY study is among the first population-based longitudinal studies to examine the mental health impact of the pandemic. The objective of the study was to assess changes in health-related quality of life (HRQoL) and mental health in children and adolescents and to identify the associated risk and resource factors during the pandemic. METHODS: A nationwide longitudinal survey was conducted with two waves during the pandemic (May/June 2020 and December 2020/January 2021). In total, n = 1923 children and adolescents aged 7 to 17 years and their parents participated (retention rate from wave 1 to wave 2: 85%). The self-report and parent-proxy surveys assessed HRQoL (KIDSCREEN-10), mental health problems (SDQ with the subscales emotional problems, conduct problems, hyperactivity, and peer problems), anxiety (SCARED), depressive symptoms (CES-DC, PHQ-2) and psychosomatic complaints (HBSC-SCL). Mixed model panel regression analyses were conducted to examine longitudinal changes in mental health and to identify risk and resource factors. RESULTS: The HRQoL of children and adolescents decreased during the pandemic, and emotional problems, peer-related mental health problems, anxiety, depressive and psychosomatic symptoms increased over time, however the change in global mental health problems from wave 1 to wave 2 was not significant, and some changes were negligible. Socially disadvantaged children and children of mentally burdened parents were at particular risk of impaired mental health, while female gender and older age were associated with fewer mental health problems. A positive family climate and social support supported the mental health of children and adolescents during the pandemic. DISCUSSION: Health promotion, prevention and intervention strategies could support children and adolescents in coping with the pandemic and protect and maintain their mental health.