Purpose Patients' understanding of their illness is key for making informed treatment decisions, yet studies suggest an association between prognostic awareness and worse quality of life (QOL) and mood among patients with advanced cancer. We sought to explore the relationships among prognostic awareness, coping, QOL, and mood in patients with newly diagnosed, incurable cancer. Methods We assessed patients' self-reported health status and treatment goal (Prognosis and Treatment Perceptions Questionnaire), coping (Brief COPE), QOL (Functional Assessment of Cancer Therapy-General), and mood (Hospital Anxiety and Depression Scale) within 8 weeks of incurable lung or GI cancer diagnosis. We used linear regression to examine associations and interaction effects among patients' health status and treatment goal, coping strategies, QOL, and mood. Results Patients who reported a terminally ill health status had worse QOL (unstandardized coefficient [B] = -6.88; P < .001), depression (B = 1.60; P < .001), and anxiety (B = 1.17; P = .007). Patients who reported their oncologist's treatment goal was "to cure my cancer" had better QOL (B = 4.33; P = .03) and less anxiety (B = -1.39; P = .007). We observed interaction effects between self-reported health status and treatment goal and certain coping strategies. Specifically, subgroup analyses showed that greater use of positive reframing was related to better QOL (B = 2.61; P < .001) and less depression (B = -0.78; P < .001) among patients who reported a terminally ill health status. Active coping was associated with better QOL (B = 3.50; P < .001) and less depression (B = -1.01; P < .001) among patients who acknowledged their oncologist's treatment goal was not "to cure my cancer." Conclusion Prognostic awareness is related to worse QOL and mood in patients with newly diagnosed, incurable cancer; however, the use of certain coping strategies may buffer these relationships. Interventions to improve patients' prognostic awareness should seek to cultivate more adaptive coping strategies in order to enhance QOL and mood.