Objective: Psychological distress remains a major challenge in cancer care. The complexity of psychological symptoms in cancer patients requires multifaceted symptom management tailored to individual patient characteristics and active patient involvement. We assessed the relationship between resilience, psychological distress and physical activity in cancer patients to elucidate potential moderators of the identified relationships. Method: A cross-sectional observational study to assess the prevalence of symptoms and supportive care needs of oncology patients undergoing chemotherapy, radiotherapy or chemo-radiation therapy in a tertiary oncology service. Resilience was assessed using the 10-item Connor-Davidson Resilience Scale (CD-RISC 10), social support was evaluated using the 12-item Multidimensional Scale of Perceived Social Support (MSPSS) and both psychological distress and activity level were measured using corresponding subscales of the Rotterdam Symptom Checklist (RSCL). Socio-demographic and medical data were extracted from patient medical records. Correlation analyses were performed and structural equation modeling was employed to assess the associations between resilience, psychological distress and activity level as well as selected socio-demographic variables. Results: Data from 343 patients were included in the analysis. Our revised model demonstrated an acceptable fit to the data (χ2(163) = 313.76, p = .000, comparative fit index (CFI) = .942, Tucker-Lewis index (TLI) = .923, root mean square error of approximation (RMSEA) = .053, 90% CI [.044.062]). Resilience was negatively associated with psychological distress (β = -.59), and positively associated with activity level (β = .20). The relationship between resilience and psychological distress was moderated by age (β = -0.33) but not social support (β = .10, p = .12). Conclusion: Cancer patients with higher resilience, particularly older patients, experience lower psychological distress. Patients with higher resilience are physically more active. Evaluating levels of resilience in cancer patients then tailoring targeted interventions to facilitate resilience may help improve the effectiveness of psychological symptom management interventions.