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Background: The COVID-19 pandemic has significantly disrupted the lives of children and adolescents worldwide. Numerous cross-sectional studies indicate high levels of emotional and behavioral problems and a decrease in health-related quality of life (HRQoL) in children and adolescents during the first months of the pandemic. However, longitudinal studies on changes in HRQoL and mental health in children and adolescents during the pandemic are limited. The German COPSY study is one of the first representative longitudinal studies to examine the impact of the COVID-19 pandemic on HRQoL and mental health in children and adolescents in two waves during the COVID-19 pandemic. Methods: A representative online survey was conducted between May and June 2020 among n = 1,586 families with 7- to 17-year-old children and adolescents. The second wave was conducted between December 2020 and January 2021 and included n = 1,625 families, of whom n = 1,288 had already participated in the first wave. The data collected was compared with pre-pandemic reference data from the representative BELLA and HBSC studies. The self-report and parent-proxy versions of the survey included internationally established instruments for measuring HRQoL (KIDSCREEN-10), mental health problems (SDQ), anxiety (SCARED), depressive symptoms (CES-DC) and psychosomatic complaints (HBSC-SCL). Results: The majority of the children and adolescents reported being burdened by the COVID-19 pandemic in both waves of the study. In the second wave, the proportions of children and adolescents reporting low HRQoL, anxiety, depressive symptoms and psychosomatic complaints had increased compared both to pre-pandemic data and to the first wave. Socially disadvantaged children as well as the children of mentally ill parents were at risk of being particularly adversely affected. A positive family climate was found to be an important resource mitigating the burden caused by the pandemic. Discussion: Health promotion, prevention and early intervention strategies need to be implemented to support children and adolescents in coping with the COVID-19 pandemic and to protect and maintain their HRQoL and mental health.