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Introduction: Socioeconomic inequalities have been associated with poorer mental health outcomes in children and adolescents during the COVID-19 pandemic. Despite numerous studies on individual risk factors, the impact of societal environment, such as neighborhood characteristics, on changes in mental health has rarely been investigated. This study investigates the effect of neighborhood deprivation on mental health problems and health-related quality of life (HRQoL) in children and adolescents during the COVID-19 pandemic in Hamburg, Germany., Methods: Data were derived from the prospective German COPSY Hamburg study. Children and adolescents aged between 11-20 years and their parents participated in the study, which took place in summer 2020 (T1) and summer 2022 (T2). Neighborhood deprivation was assessed by a neighborhood status index. Mental health problems and HRQoL were assessed using internationally validated and established instruments. The prevalence of mental health problems and impaired HRQoL was reported. Analysis of covariance was conducted to examine the effect of neighborhood deprivation of the districts in Hamburg on the (changes in) mental health problems and HRQoL while controlling for social individual-level indicators., Results: The total sample included in the statistical analysis consisted of N = 2,645 families. Children and adolescents living in more deprived areas had higher levels of general mental health problems and depressive symptoms during the COVID-19 pandemic. However, differences in neighborhood deprivation did not relate to the HRQoL and the averaged changes in children and adolescents' mental health problems and HRQoL from summer 2020 to summer 2022., Discussion: Neighborhood deprivation is associated with impaired mental health in youth during the COVID-19 pandemic. Children and adolescents' mental health and overall well-being should be addressed by health promotion measures to create a health-promoting living environment, including diverse neighborhoods. Future research should focus on uniform assessment methods and addressing additional neighborhood factors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)