<p>Climate change threatens human health, but its psychological effects on young people remains relatively understudied. Conversely, ample evidence demonstrates that Physical Activity (PA) positively impacts the psychological well-being in young people. Thus, this cross-sectional study investigated whether PA moderates the impact of a large flood experience on the relationship between eco-anxiety and well-being in young people. One thousand twenty-one (<i>N</i> = 1.021) adolescents aged 9 to 16 years old (<i>M</i>age = 12.35 ± 1.38) completed measures for PA frequency, flood experience, eco-anxiety, and psychological well-being, six month after Daniel extreme flood event in Greece. Moderated moderation analysis was conducted to test the hypothesized model using PROCESS macro. We examined whether the relationship between eco-anxiety and well-being was moderated by flood experience alone, PA frequency alone, and/or flood experience and PA frequency combined. However the three-way interaction predicted only a very small of unique variance in well-being, Δ<i>R</i>^<i>2</i> = 0.007. Further examination of the three-way interaction showed that when PA frequency scores were lower than 2.71 days/week, flood experience potentiated the negative effect of eco-anxiety on well-being. In contrast, the moderating influence of flood experience on the relationship between eco-anxiety and well-being was buffered when PA frequency scores were higher than 6.25 days/week. Findings provide initial support that frequent PA participation (6–7 days /week) may improve the well-being of children and adolescents in times of crisis, potentially by reducing the effect of flood-related experience on the negative relationship between eco-anxiety and well-being.</p>