Background: Homeless youth, as a vulnerable population are susceptible to various mental and health risk behaviours. However, less is known of the mental health status of these homeless youth and its role in risky sexual behaviours; neither do we understand the reasons homeless youth give for their engagement in various health risk behaviour. Objective: The main purpose of this study was in three fold: (1) to explore the reasons for homeless youth engagement in health risk behaviours; (2) to determine the relationship between substance use and sexual risks behaviours and (3) to determine the factors related to their psychological functioning. Method: An exploratory sequential mixed methods design was used to collect data from 227 homeless youth recruited from Accra, Ghana. Thematic analysis was used to analyse the transcripts of 16 homeless youth who revealed their experiences of how they live their life on the street. Results: Of the 227 participants in the study, 199 (87.6 %) exhibited moderate to severe psychological problems. Violent behaviour, suicidal ideation and stigma (both self and social stigma) significantly predicted overall psychological functioning. Substance use among street youth particularly alcohol use, marijuana and cigarette smoking were independently associated with having unprotected sex, multiple sexual partners and engagement in survival sex. Engagements in risky behaviours were primary focused on survival strategies, and the emotional impact of homelessness was evidenced in their feelings of exclusion due to social stigma and feelings of despondency and depression. Conclusion: The findings in this study calls for a more holistic interventions to help improve the health and wellbeing of street-connected youth. Such interventions should address concurrent substance use and sexual risk behaviours, and improved access to psychological health services.