Social isolation and loneliness pose major societal challenges whose global spread has been accelerated by the COVID-19 pandemic. Therefore, finding accessible and effective resilience strategies that mitigate the negative affective impact of social isolation on mental health is a top priority.In a cohort study with 317 young adults (mean[SD] age, 23.08 [2.83] years; 181 females [57.09%]), utilizing accelerometry, electronic diaries, and functional neuroimaging, we examined the effectiveness of physical activity in offsetting affective loss due to social isolation in everyday life and investigate the associated neural risk signatures.We found that lacking social contact negatively impacts daily affective well-being. However, engaging in physical activity, even at minimal doses (P < 0.04), serves as a compensatory mechanism (P=0.020). Especially vulnerable individuals with higher default mode network (DMN) connectivity (P=0.029), a risk phenotype for loneliness and depression, benefit most from this positive effect.Our study elucidates the dynamic interplay between social contact, physical activity, and mental well-being, offering a viable strategy to mitigate the negative impacts of social isolation, particularly among at-risk individuals. These findings hold significant implications for public health, emphasizing the importance of integrating physical activity interventions into strategies for managing social isolation in both current and post-pandemic contexts.