The Affordable Care Act (ACA) offered an unprecedented opportunity to expand insurance coverage to patients with substance use disorders (SUDs). We explored the expectations of key stakeholders for the ACA’s impact on SUD care, and examined how clinical characteristics of newly enrolled patients with SUD in a large healthcare delivery system differed pre- and post- ACA implementation. In this mixed-methods study, qualitative interviews were conducted with health system leaders to identify themes regarding how the health system prepared for the ACA. Electronic health record data were used to examine demographics, as well as specific SUD, psychiatric, and medical diagnoses in cohorts of pre-ACA (2012, n = 6066) vs. post-ACA (2014, n = 7099) newly enrolled patients with SUD. Descriptive statistics and logistic regression models were employed to compare pre-ACA and post-ACA measures. Interviewees felt much uncertainty, but anticipated having to care for more SUD patients, who might have greater severity. Quantitative findings affirmed these expectations, with post-ACA SUD patients having higher rates of cannabis and amphetamine use disorders, and more psychiatric and medical conditions, compared to their pre-ACA counterparts. The post-ACA SUD cohort also had more Medicaid patients and greater enrollment in high-deductible plans. Post-ACA, SUD patients had more comorbidities as well as and more financial barriers to care. As federal healthcare policy continues to evolve, with potentially more restrictive coverage criteria, it is essential to continue examining how health systems adapt to changing health policy and its impact on SUD care.