Unhealthy substance use in the USA results in significant mortality and morbidity. This study measured the effectiveness of paraprofessional-administered substance use screening, brief intervention, and referral to treatment (SBIRT) services on subsequent healthcare utilization and costs. The pre-post with comparison group study design used a population-based sample of Medicaid patients 18-64 years receiving healthcare services from 33 clinics in Wisconsin. Substance use screens were completed by 7367 Medicaid beneficiaries, who were compared to 6751 randomly selected treatment-as-usual Medicaid patients. Compared to unscreened patients, those screened changed their utilization over the 24-month follow-up period by 0.143 outpatient days per member per month (PMPM) (p < 0.001), -0.036 inpatient days PMPM (p < 0.05), -0.001 inpatient admissions PMPM (non-significant), and -0.004 emergency department days PMPM (non-significant). The best estimate of net annual savings is $391 per Medicaid adult beneficiary (2014 dollars). SBIRT was associated with significantly greater outpatient visits and significant reductions in inpatient days among working-age Medicaid beneficiaries in Wisconsin.