Background: Oncology Care Model (OCM) requires cancer programs to provide depression screening during each care episode to meet the quality measure benchmark of 85% screening rate. This quality improvement (QI) project aims to assess 1) key strategies to integrate system-wide depression screening into routine cancer care, and 2) early outcomes of depression screening implementation. Methods: A mixed-method study design was used to assess strategies to implement routine depression screening in a southeast comprehensive cancer center between July 2019 and December 2020. Two top high-volume hematological oncology clinics that covers sixty percent of ambulatory care participated in the depression screening implementation. Data were collected using 1) depression screening completion rate during OCM performance periods, 2) needs assessment to identify barriers and facilitators of implementation, and 3) semi-structured interviews to assess staff and provider feedback on sustainable implementation strategies. Data were analyzed using descriptive analysis for quantitative outcomes and thematic analysis for qualitative outcomes. Results: A total of 64 hematological oncology providers (n = 22) and staff (n = 42) participated in the depression screening implementation training during three OCM performance periods. Depression screening rate of total ambulatory oncology care increased from 12% (OCM-PR 5, Jul-Dec 19), to 51% (OCM-PR 6, Jan-Jun 20) to 77% (OCM-PR 7, Jul-Dec 20) after the two top-volume clinics integrated depression screening into clinic intake process. Themes emerged from needs assessment revealed multi-level implementation strategies including 1) patient education and psycho-oncological care, 2) staff training and practice modification, 3) provider education & interdisciplinary Care, 4) leadership, administration, and staffing support, and 5) clinical informatics collaboration to build the infrastructure for integrating depression screen with clinic intake in the electronic medical record (EMR). Feedback from staff and provider interviews indicated high receptiveness and buy-in, especially during the COVID-19 pandemic to improve timely identification and triage of patients with depressive symptoms across all oncology care services. Conclusions: Depression screening is a key component of quality comprehensive cancer care that aims to provide timely identification and triage of cancer patients needing follow-up psychosocial care. Early implementation outcomes revealed significant improvement in depression screening completion rate after two clinics adopted depression screening into intake process. Further investigation is needed to refine system-wide implementation strategies across all ambulatory oncology sites and to assess long-term implementation outcomes meet the psychosocial care needs of cancer patients.