Four personality risk profiles have been related to higher risk of substance misuse and mental health disorders among general populations of adolescents: impulsivity (IMP), sensation seeking (SS), hopelessness (HOP), and anxiety sensitivity (AS). Based on these previous findings, we tested the hypotheses that, in adolescents living in vulnerable contexts: 1) the 2 internalizing personality profiles (HOP, AS) would be related to internalizing symptoms (depressive, anxiety) and PTSD and complex-PTSD, whereas, 2 externalizing personality profiles (SS, IMP) would be related to externalizing symptoms (conduct, hyperactivity/inattentive); and 2) all personality profiles would be related to frequencies of alcohol and cannabis use and binge drinking. Participants were 62 adolescents (52% female; Mean age = 16.07 years) temporarily residing at 8 different youth protection units across the City of Montreal. Adolescents were assessed using the Substance Use Risk Profile Scale (SURPS) for 4 personality profiles and other self-report questionnaires for past-year substance use and mental health disorders. Univariate regression analysis was used to examine the relationship between 4 types of personality profiles, when simultaneously entered in the model, and each outcome. Over and above other personality risk profiles: higher AS, HOP, and SS were related to higher internalizing symptoms (t = 3.33, p < 0.01; t = 4.22, p < 0.001; t = 2.02, p < 0.05, respectively), whereas higher IMP was associated with higher externalizing symptoms (t = 5.00, p < 0.001). HOP was positively associated with complex-PTSD (β = 1.24; p < 0.05) and higher frequencies of alcohol (t = 2.13; p < 0.05) and cannabis (t = 2.28; p < 0.05) use. SS was positively related to binge drinking (t = 2.37; p < 0.05). The present study replicated some of the prior findings regarding the associations of personality profiles and risk of specific mental illness symptoms/disorders and additionally highlighted the role of HOP in the risk of substance misuse in adolescents living in vulnerable contexts. Efforts to reduce such risk in this population might benefit from personality-targeted interventions, which have been shown to prevent substance misuse and mental illness symptoms in students attending mainstream high schools.