Comorbid substance use in adolescents with mental illness is often an indicator of poor treatment outcome. This study aims to determine the prevalence of, and associated risk factors for, substance use in adolescents with mental illness attending a mental health service. Data was collected from hospital records of 162 adolescents, using a structured data sheet, over a two-year period. Substance use was more significant in older adolescents and those with severe mental illness. Sixty-two (38.3%) adolescents used substances. Thirty-seven (38.1%) male adolescents reported substance use compared to 25 (38.5%) female adolescents. Alcohol was the most commonly used substance (n = 48; 29.6%), followed by cannabis (n = 32; 19.8%). There were significant direct associations between substance use and history of abuse or neglect, forensic history, educational setting, admission status, and the psychiatric diagnoses of schizophrenia, other psychotic disorders, and bipolar mood disorder. Inverse associations were found between substance use and adjustment disorders, attention deficit hyperactivity disorder, and intellectual disability. The results of this study indicate an urgent need for substance misuse programmes for at risk youth, and the introduction of dual diagnosis intervention programmes in this age group.