<p>Depressive symptoms are widely prevalent among patients with head and neck cancer but frequently remain unaddressed. The objective of this study was to examine the relationships among post-traumatic growth, coping strategies, resilience, and depression, with a particular focus on investigating whether depression serves as a moderating factor in the connection between selected variables and resilience. A cross-sectional study included a cohort of 228 individuals diagnosed with head and neck cancer. Patients completed questionnaires, which included the “Connor-Davidson Resilience Scale,” “Post-Traumatic Growth Inventory,” “Brief COPE,” and “Hospital Anxiety and Depression Scale.” The relationship among post-traumatic growth, coping, depression, and the interaction between post-traumatic growth/coping × depression with resilience was analyzed using hierarchical multiple regression. The interaction was illustrated through a simple slope analysis. 42.4% of the head neck cancer patients reported depression in our study. Post-traumatic growth and coping were related to resilience. Depression could moderate the association between them and resilience. The depression level was higher, post-traumatic growth, and coping had a weaker impact on resilience. Medical staff should systematically evaluate the internal environmental factors related to patients’ quality of life and help patients relieve their emotional distress caused by the disease through positive psychological guidance.</p>