Recent trends in Switzerland indicate a concerning rise in simultaneous polysubstance use among adolescents, a practice marked by the concurrent or sequential consumption of multiple psychoactive substances, notably alcohol and cannabis, alongside prescription medications (e.g. benzodiazepines) and illicit drugs, resulting in dozens of fatal outcomes. However, data on simultaneous polysubstance use and evidence-based approaches to effective prevention is lacking. The study aimed to explore and gain insights into use patterns, use settings, use motives, harm-reduction strategies, concerns associated with substance use, and support and counselling services from the point of view of adolescents practicing simultaneous polysubstance use in Switzerland. An exploratory study was conducted via an online survey (n = 116) and two focus group discussions with affected Swiss adolescents aged 14 to 20. A mixed-methods approach was applied to gain insights and better understand the phenomenon of simultaneous polysubstance use among Swiss adolescents. Quantitative survey data obtained between November 2021 and March 2023 by means of convenience sampling - organised by distributing flyers (in three national languages) among several project partners, on the internet, over social media and by word of mouth - was analysed descriptively, whereas qualitative survey data and focus group data were thematically explored. A concurrent nested design was employed, utilising quantitative findings as a core foundation for addressing research questions, while qualitative findings were instrumental in validating and providing contextual depth to the results. Our findings reveal a preference of the sample for combining alcohol with cannabis and/or other substances (e.g. benzodiazepines or hard drugs) in social settings, driven by diverse motives, including enhancement of experiences and partly maladaptive coping mechanisms leading to self-medication. Despite some awareness of the potential harms, there is a significant reliance on peer-shared strategies for harm reduction, highlighting a gap in formal support and counselling services, some of which are perceived by adolescents as lacking empathy and relevance. This study underscores the urgency of developing targeted, youth-centred interventions that resonate with the lived realities of adolescents, aiming not only to reduce substance use but also to address the broader psychosocial factors contributing to simultaneous polysubstance use. By shedding light on the complex dynamics of adolescent polysubstance use, our research contributes to the ongoing dialogue on effective prevention strategies, advocating for a holistic approach encompassing education, policy reform and community support to tackle this multifaceted public health challenge.