Introduction: COVID-19 lockdown measures resulted in children and adolescents staying and learning at home. This study investigated health-related quality of life (HRQoL) and its associated factors among youth during the first lockdown. Methods: A cross-sectional study was conducted among 8-to 18-year-olds from the French Grand Est region. Sociodemographic data and information on living and learning conditions were collected using an online survey. HRQoL was assessed using the KIDSCREEN-27. Multiple regression analysis was performed to explore factors related to low HRQoL in each dimension. Results: In total, 471 children from 341 households were included. Difficulties isolating at home were associated with low HRQoL in the psychological well-being (OR = 2.2, 95% CI: 1.2-4.0) and parent relations and autonomy (OR = 2.1, 95% CI: 1.2-3.8) dimensions. Conflicts with dwelling occupants were related to increased ORs in the psychological well-being (OR = 2.9, 95% CI: 1.9-4.6), parent relations and autonomy (OR = 2.2, 95% CI: 1.4-3.4) and school environment (OR = 2.4, 95% CI: 1.5-3.7) dimensions. Living in an apartment (OR = 1.8, 95% CI: 1.1-3.1), never leaving home (OR = 2.6, 95% CI: 1.2-5.9), having indoor noise at home (OR = 2.3, 95% CI: 1.2-4.6), and having a parent with high anxiety (OR = 1.8, 95% CI: 1.1-3.1) were associated with low HRQoL in the social support and peers dimension. Children working less than 1 h/day on schoolwork had an increased OR of 3.5 (95% CI: 1.4-9.0) in the school environment dimension. Conclusion: Living and learning conditions were associated with low HRQoL among children and adolescents during the COVID-19 lockdown. Prevention and intervention programs are needed to support youth by facilitating their interactions and improving their coping and to prepare for future waves.