Background: Public health measures to curb SARS-CoV-2 transmission rates may have negative psychosocial consequences in youth. Digital interventions may help to mitigate these effects. We aimed to investigate the associations between social isolation, COVID-19-related worries/anxieties, objective social risk indicators, psychological distress and use of digital mobile health (mHealth) interventions in youth during the COVID-19 pandemic.Methods: Data were collected as part of the “Health And Innovation During COVID-19 Survey” —a cross-sectional panel study including a representative sample of individuals aged 16 to 25 years (N=666; Mage 21·3) (assessment period: 07.05.-16.05.2020). Data were collected on social isolation, COVID-19-related worries/anxieties, objective social risk indicators, psychological distress as well as the current use of and attitude towards digital interventions.Outcomes: Social isolation, lack of company, worrying, and objective social risk indicators were associated with psychological distress during the COVID-19 pandemic. Dose-response relationships were found. For instance, psychological distress was progressively more likely to occur as levels of reported social isolation increased (with reporting ‘never’ as reference group: ‘very rarely’: adjusted odds ratio [aOR] 2·4,CI 1·0 – 5·7, p=0·041; ‘rarely’: aOR 3·6, CI 1·7 – 7·7, p=0·001; ‘occasionally’: aOR 8·4, CI 4·0 – 17·5, p<0·001; ‘often’: aOR 20·6, CI 9·3 – 45·7, p<0·001;’very often’: aOR 43·4, CI 14·7 – 128·2, p<0·001). There was evidence that psychological distress, and high levels of social isolation, lack of company, and worrying were associated with a positive attitude towards using digital interventions, whereas only severe levels of psychological distress and worries were associated with actual use (aOR 2·0, CI 1·3 - 3·0, p=0·001; aOR 1·6, CI 1·1 – 2·2, p=0·005, respectively).Interpretation: Public health measures during pandemics may be associated with social isolation and poor mental health outcomes in youth. Digital interventions may help mitigate the negative psychosocial impact without risk for viral infection given there is an objective need and subjective demand.