More than 61,000 persons below the age of 18 are living on the streets in the Greater Accra region in Ghana. Street children is a hidden vulnerable population and a global public health issue in the world, but little is known about their mental health and health needs, and mechanisms that contribute to their poor health. With a lack of mental health research to guide intervention or psychoeducation programme and policy planning, this study aimed to address these research gaps by examining prevalence of mental health problems and a set of associated risk factors (i.e. Perceived quality of life, and social connection). In addition, we examined whether the associations between risk factors and mental health problems were moderated by demographic and contextual factors (i.e., gender, age, work status, reason for living on street, number of years in street). Two hundred and seven children between age 12 and 18 who lived on the street in three cities (Accra, Sekondi Takoradi, and Kumasi) were recruited. Data were gathered through adolescent survey/interviews. Multiple regression was utilized to examine risk factors and moderation effects. Results support high mental health needs among street children. Approximately 73% street children experienced moderate to severe mental health problems, and 90% experienced poor quality of life. Perceived quality/happiness of life was the strongest predictor for street children’s mental health. Social connection was associated with children’s mental health only in certain subgroups and contexts. This study adds new epidemiological evidence for street children, an extremely vulnerable population, in Ghana and global child and adolescent mental health.