Background: Machine learning models are well-positioned to transform cancer care delivery by providing oncologists with more accurate or accessible information to augment clinical decisions. Many machine learning projects, however, focus on model accuracy without considering the impact of using the model in real-world settings and rarely carry forward to clinical implementation. We present a human-centered systems engineering approach to address clinical problems with workflow interventions utilizing machine learning algorithms. Methods: We aimed to develop a mortality predictive tool, using a Random Forest algorithm, to identify oncology patients at high risk of death within 30 days to move advance care planning (ACP) discussions earlier in the illness trajectory. First, a project sponsor defined the clinical need and requirements of an intervention. The data scientists developed the predictive algorithm using data available in the electronic health record (EHR). A multidisciplinary workgroup was assembled including oncology physicians, advanced practice providers, nurses, social workers, chaplain, clinical informaticists, and data scientists. Meeting bi-monthly, the group utilized human-centered design (HCD) methods to understand clinical workflows and identify points of intervention. The workgroup completed a workflow redesign workshop, a 90-minute facilitated group discussion, to integrate the model in a future state workflow. An EHR (Epic) analyst built the user interface to support the intervention per the group’s requirements. The workflow was piloted in thoracic oncology and bone marrow transplant with plans to scale to other cancer clinics. Results: Our predictive model performance on test data was acceptable (sensitivity 75%, specificity 75%, F-1 score 0.71, AUC 0.82). The workgroup identified a “quality of life coordinator” who: reviews an EHR report of patients scheduled in the upcoming 7 days who have a high risk of 30-day mortality; works with the oncology team to determine ACP clinical appropriateness; documents the need for ACP; identifies potential referrals to supportive oncology, social work, or chaplain; and coordinates the oncology appointment. The oncologist receives a reminder on the day of the patient’s scheduled visit. Conclusions: This workgroup is a viable approach that can be replicated at institutions to address clinical needs and realize the full potential of machine learning models in healthcare. The next steps for this project are to address end-user feedback from the pilot, expand the intervention to other cancer disease groups, and track clinical metrics.