Patients with cancer and multiple chronic conditions (complex cancer survivors) are vulnerable to the negative impacts of COVID-19. However, their experiences and coping strategies during the COVID-19 pandemic have not been extensively studied. A mixed-methods design was used to assess coping strategies and protective responses taken to minimize COVID-19 infection. Participants were drawn from a cohort of complex cancer survivors from a pragmatic clinical trial. Participants reported high adherence to recommended protective behaviors, and risk was assessed based on comorbidities, not cancer status. Most did not experience significant disruptions in cancer-related or primary health care but experienced pandemic-related emotional stressors. Participants managed the impact of the pandemic using spirituality, support from social networks, and coping lessons from their cancer experience.