Background: Delivering evidence-based tobacco dependence treatment in oncology settings improves smoking abstinence and cancer outcomes. Leadership engagement/buy-in is critical for implementation success, but few studies have defined buy-in or described how to secure buy-in for tobacco treatment programs (TTPs) in cancer care. This study examines buy-in during the establishment of tobacco treatment programs at National Cancer Institute (NCI)-designated cancer centers. Methods: We utilized a sequential, explanatory mixed-methods approach to analyze quantitative data and qualitative interviews with program leads in the U.S.-based NCI Moonshot-supported Cancer Center Cessation Initiative (n = 20 Centers). We calculated descriptive statistics and applied structural coding and content analysis to qualitative data. Results: At least 75% of participating centers secured health care system administrative, clinical, and IT leadership buy-in and support. Six themes emerged from interviews: engaging leadership, access to resources, leveraging federal funding support to build leadership interest, designating champions, identifying training needs, and ensuring staff roles and IT systems support workflows. Conclusions: Buy-in among staff and clinicians is defined by the belief that the TTP is necessary, valuable, and evidence based. Recognizing and securing these dimensions of buy-in can facilitate implementation success, leading to improved cancer outcomes.