Background <p>Physical activity (PA) interventions may benefit youth with problematic substance use (SU); however, the acceptability of these interventions in young people is poorly understood. In this mixed-methods study, predictors and correlates of treatment acceptability of PA interventions as part of SU treatment were investigated, and young people’s perspectives on PA intervention (e.g., perceived barriers and service-related needs) were explored.</p> Methods <p>Young people aged 16-25 years (n=145) with problematic SU completed a quantitative online survey on substance use, PA engagement, treatment acceptability, and perceived barriers and benefits of PA. Data were analysed using data mining and modelling approaches. Four participants aged 18-25 years participated in a subsequent, semi-structured focus group; data were analysed using qualitative content analysis. Quantitative and qualitative findings were integrated using an established model of behaviour change (COM-B). </p> Results <p>Generalised additive modelling identified perceived PA barriers to be a predictor of treatment acceptability (<i>p</i>≤.001). Decision tree analyses confirmed that lower psychological distress (1^st partition, <i>p</i>&lt;.001) and higher PA levels (2^nd partition, <i>p</i>=.03) predicted lower perceived PA barriers. Latent class analysis suggested a 2-class model differentiating young people at moderate substance-related risk, reporting low psychological distress and perceived PA barriers (class 1) from young people at severe substance-related risk, reporting higher psychological distress and perceived barriers. Qualitative findings revealed substantial barriers to PA, including substance-related, mental health, access, and social barriers. Together, findings illustrated complex interactions between different dimensions related to behaviour change and areas where clinical services may increase young people’s capability, opportunity and motivation to prompt behaviour change.</p> Conclusions <p>PA levels and psychological distress predict perceived barriers to PA in young people with problematic SU. PA barriers predict treatment acceptability of PA interventions. Knowledge of such predictors may inform treatment decisions by clinicians. Young people’s insights should be integrated into PA intervention research to inform intervention and understand the unique barriers, preferences and needs of youth affected by problematic SU. Integration of young people’s perspectives may increase behaviour change, as well as motivation, engagement and positive feelings in young people participating in PA interventions within substance use treatment.</p>