Screening, brief intervention, and referral to treatment (SBIRT) for adolescents exhibiting co-occurring substance use and mental health problems may improve outcomes and have long-lasting effects. This study examined the relationship between access to SBIRT and substance use, depression and medical diagnoses, and health services use at 1 and 3 years postscreening for such adolescents. The study draws from a cluster-randomized trial comparing SBIRT to usual care (UC) for adolescents endorsing past-year substance use and recent mood symptoms during visits to a general pediatrics clinic between November 1, 2011, and October 31, 2013, in a large, integrated health system (N = 1851); this sample examined the subset of adolescents endorsing both problems (n = 289). Outcomes included depression, substance use and medical diagnoses, and emergency department and outpatient visits 1 and 3 years later. The SBIRT group had lower odds of depression diagnoses at 1 (odds ratio [OR] = 0.31; confidence interval [CI] = 0.11-0.87) and 3 years (OR = 0.51; CI = 0.28-0.94) compared with the UC group. At 3 years, the SBIRT group had lower odds of a substance use diagnosis (OR = 0.46; CI = 0.23-0.92), and fewer emergency department visits (rate ratio = 0.65; CI = 0.44-0.97) than UC group. The findings suggest that SBIRT may prevent health complications and avert costly services use among adolescents with both mental health and substance use problems. As SBIRT is implemented widely in pediatric primary care, training pediatricians to discuss substance use and mental health problems can translate to positive outcomes for these vulnerable adolescents.