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Background Over a million adolescents die globally each year from preventable or treatable causes, with injuries (intentional and unintentional) being the leading cause of these deaths. To inform strategies to prevent these injuries, we aimed to assess psychosocial factors associated with serious injury occurrence, type, and mechanism in adolescents. Methods and findings We conducted a secondary analysis of cross-sectional survey data collected from the Global School-based Student Health Survey between 2009 and 2015. We used logistic regression to estimate associations between prevalence of serious injuries, injury type (effects of injury), and injury mechanism (cause of injury) and psychosocial factors (factors that relate to individuals socially, or their thoughts or behaviour, or the interrelation between these variables). Psychosocial factors were categorised, based on review of the literature, author knowledge, and discussion amongst authors. The categories were markers of risky behaviour (smoking, alcohol use, drug use, and physical activity), contextual factors (hunger, bullying, and loneliness), protective factors (number of friends and having a supportive family), and markers of poor mental health (planned or attempted suicide and being too worried to sleep). Models were adjusted for country factors (geographical area and income status, both using World Bank classification), demographic factors (age and sex), and factors to explain the survey design. A total of 87,269 adolescents living in 26 countries were included. The weighted majority were 14–15 years old (45.88%), male (50.70%), from a lower-middle-income country (81.93%), and from East Asia and the Pacific (66.83%). The weighted prevalence of a serious injury in the last 12 months was 36.33%, with the rate being higher in low-income countries compared to other countries (48.74% versus 36.14%) and amongst males compared to females (42.62% versus 29.87%). Psychosocial factors most strongly associated with serious injury were being bullied (odds ratio [OR] 2.45, 95% CI 1.93 to 3.13, p < 0.001), drug use (OR 2.08, 95% CI 1.73 to 2.49, p < 0.001), attempting suicide (OR 1.78, CI 1.55 to 2.04, p < 0.001), being too worried to sleep (OR 1.80, 95% CI 1.54 to 2.10, p < 0.001), feeling lonely (OR 1.61, 95% CI 1.37 to 1.89, p < 0.001), and going hungry (OR 1.61, 95% CI 1.30 to 2.01, p < 0.001). Factors hypothesised to be protective were not associated with reduced odds of serious injury: Number of close friends was associated with an increased odds of injury (OR 1.23, 95% CI 1.06 to 1.43, p = 0.007), as was having understanding parents or guardians (OR 1.13, 95% CI 1.01 to 1.26, p = 0.036). Being bullied, using drugs, and attempting suicide were associated with most types of injury, and being bullied or too worried to sleep were associated with most mechanisms of injury; other psychosocial factors were variably associated with injury type and mechanism. Limitations include the cross-sectional study design, making it not possible to determine the directionality of the associations found, and the survey not capturing children who did not go to school. Conclusions We observed strong associations between serious injury and psychosocial factors, but we note the relationships are likely to be complex and our findings do not inform causality. Nevertheless, our findings suggest that multifactorial programmes to target psychosocial factors might reduce the number of serious injuries in adolescents, in particular programmes concentrating on reducing bullying and drug use and improving mental health., In an analysis of data from the Global Schools-Based Student Health Survey, Samiha Ismail, Maria Odland, and colleagues investigate the relationships between serious injuries and psychosocial factors among adolescents across 26 countries., Author summary Why was this study done? Globally, the leading cause of disability-adjusted life years in adolescents is road traffic injuries (self-harm and interpersonal violence are also in the top 5), and there is an urgent need to reduce this preventable burden of injuries. Poor mental health and challenging psychosocial circumstances are also known to commonly affect adolescents. This study was done to assess the association between adolescents’ mental health and psychosocial circumstances and injury in order to suggest potential points of intervention to improve outcomes. What did the researchers do and find? We quantified the association between psychosocial circumstances and serious injury occurrence, mechanism, and type in adolescents, taking into account country as well as individual factors that could affect the relationship. We found that factors and behaviours such as being bullied and using drugs were strongly associated with an increase in serious injuries, as were indicators of poor mental health such as being too worried to sleep or having attempted suicide. We also found that factors that we hypothesised to be protective, such as having close friends or understanding family members or guardians, were not significantly associated with the occurrence of serious injury, apart from in the highest categories, where they were associated with an increase in serious injuries. The relationships between psychosocial circumstances and injury were similar across world regions and countries with different income status. What do these findings mean? All available evidence points to psychosocial factors such as bullying, drug-taking, and poor mental health being strongly associated with occurrence of injury, and this association is consistent across geographical regions and countries with different income status. Our findings suggest that multifactorial programmes to target psychosocial factors might reduce the number of serious injuries in adolescents across different countries and contexts. In particular, concentrating on reducing bullying and drug use and improving mental health could reduce the number of serious injuries among adolescents in the future.