Abstract: The COVID-19 pandemic has induced new and exacerbated existing stressors. From a resilience framework perspective, we investigated which potentially protective individual and family factors are negatively associated with youth depression symptoms (DS) during COVID-19 and to what extent these associations are attributable to genetic and environmental factors. We considered 3,025 monozygotic and dizygotic twins in their adolescence and early adulthood from a representative German twin family sample. Multiple regression models yielded significant effects of prepandemic DS, life satisfaction, openness to experience, and internalizing behavior. We found a substantially smaller explanatory power of the considered predictors for pandemic compared to prepandemic DS. Twin analyses showed major time-specific environmental effects. Genetic variance was fully explained by prepandemic DS, life satisfaction, openness to experience, and internalizing behavior. Consecutive increases in explanatory power across pandemic waves point toward plasticity. The findings are discussed regarding the specificity of the pandemic and the importance of individual social settings in adaptation to pandemic adversity.