With US Centers for Disease Control and Prevention funding, from 2018 to 2022, 4 large healthcare systems (n = 53 health centers across 7 states) serving people of reproductive age trained staff and provided implementation support for alcohol screening and brief intervention (SBI). This cross-site evaluation explores each healthcare system's implementation approach to implement SBI, reduce excessive alcohol use, and prevent prenatal alcohol exposure (PAE) and fetal alcohol spectrum disorders. The SBIRT (Screening, Brief Intervention, and Referral to Treatment) Program Matrix framed the multilevel strategies to implement alcohol SBI programs from 2018 to 2022. Qualitative and quantitative data sources examined outcomes, guided by one logic model, through systems-level process data and provider-level performance metrics. Data analyses utilized frequencies and means for quantitative data and themes for qualitative data according to an established framework. Successful approaches within systems included using electronic health records, flexible implementation and workflow protocols, customized training and technical assistance programs, quality assurance feedback loops, and stakeholder buy-in. Centralized management structures were efficient in standardizing implementation across health centers. Decentralized management structures used tailored approaches, enhancing provider/staff SBI acceptance. Across systems, 1259 staff (eg, clinicians, medical assistants) were trained to provide alcohol SBI services and reported pre-post training increases in self-efficacy in performing brief intervention; skills in PAE counseling; and confidence in screening. Fifty-three (48 providing data) health centers implemented alcohol SBI, screening 106 826 patients over the study period with most of the 10 087 patients who screened positive for excessive alcohol use receiving a BI. Maximizing the use of technology, employing flexibility in program delivery, and institutionalizing processes and protocols improved workflow, efficiency, and program reach. Ongoing partnership and stakeholder communication identify areas for ongoing improvement, engagement, and best practices for sustainability around substance use screening, which are essential with increases in substance use since the pandemic.