ABSTRACT: Background: Smoking rates among low-income patients are double those of the general population. Access to health care is an essential social determinant of health. Federally qualified health care centers (FQHC) are government-supported and community-based centers to increase access to health care for non-insured and underinsured patients. However, barriers to implementation impact adherence and sustainability of evidence-based smoking cessation within FQHC settings. To address this implementation barrier, our multi-disciplinary team proposes Mi QUIT CARE (Mile Square QUIT Community-Access-Referral-Expansion) to establish the acceptability, feasibility, and capacity of an FQHC system to deliver an evidence-based and multi-level intervention to increase patient engagement with a state tobacco quitline. Methods: A mixed-method approach, rooted in an implementation science framework of RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance), will be used in this hybrid effectiveness-implementation design. We aim to evaluate the efficacy of a novel delivery system (patient portal) for increasing access to smoking cessation treatment. In preparation for a future randomized clinical trial of Mi QUIT CARE, we will conduct the following developmental research: (1) Examine the burden of tobacco among patient populations served by our partner FQHC, (2) Evaluate among FQHC patients and health care providers, knowledge, attitudes, barriers, and facilitators related to smoking cessation and our intervention components, (3) Evaluate the use of tailored communication strategies and patient navigation to increase patient portal uptake among patients, and (4) To test the acceptability, feasibility, and capacity of the partner FQHC to deliver Mi QUIT CARE. Discussion: This study provides a model for developing and implementing smoking and other health promotion interventions for low-income patients delivered via patient health portals. If successful, the intervention has important implications for addressing a critical social determinant of cancer and other tobacco-related morbidities. Trial Registration: U.S. National Institutes of Health Clinical Trials, NCT04827420, https://clinicaltrials.gov/ct2/show/NCT04827420.