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We evaluated whether mental health changes differed by school learning modes during the pandemic response among Canadian adolescents and whether associations varied by gender and perceived home life.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used prospective survey data from 7270 adolescents attending 41 Canadian secondary schools. Conditional change linear mixed effects models were used to examine learning mode (virtual optional, virtual mandated, in-person, and blended) as a predictor of change in mental health scores (depression [Centre for Epidemiologic Studies \u2013 Depression], anxiety [Generalized Anxiety Disorder-7], and psychosocial well-being [Flourishing scale]), adjusting for baseline mental health and covariates. Gender and home life happiness were tested as moderators. Least square means were calculated across interaction groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Students learning in a blended learning mode had greater anxiety increases relative to their peers in other learning modes. Females learning fully in-person and males learning virtually when optional reported less of an increase in depression scores relative to their gender counterparts in other learning modes. Learning virtually when optional was associated with greater declines in psychosocial well-being in students without happy home lives relative to other learning modes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Findings demonstrate the importance of considering gender and home environments as determinants of mental health over the pandemic response and when considering alternative learning modes. Further research is advised before implementing virtual and blended learning modes. 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