Purpose Few existing interventions have effectively improved the quality of life (QOL) for patients with advanced cancer and their caregivers, partly due to limited research on the factors associated with QOL. Guided by an adapted stress-coping model, this study aimed to examine the associations between the QOL of cancer patients and their caregivers and their primary and secondary appraisals. Primary appraisals involve perceptions and evaluations of advanced cancer and related caregiving, while secondary appraisals relate to their available resources and coping capabilities. Methods Using multi-level modeling, we conducted a secondary analysis of the baseline data collected from a randomized clinical trial that examined the effects of a family-based, psychoeducational support program for patients with advanced cancer and their caregivers (N = 362 dyads). Results The appraisal variables hypothesized in the adapted stress-coping model explained 74.14% of the variance in the QOL of patients with advanced cancer and their caregivers when controlling for demographics and other disease-related variables. Better QOL in patients and caregivers was associated with less negative appraisals of illness/caregiving, less uncertainty and hopelessness, less avoidant coping strategies, more family support, more health behaviors, higher self-efficacy, and more active coping strategies. Conclusion Our study highlights the significant impact that advanced cancer has on patients and their caregivers' perceptions, responses to the illness, and QOL. It also highlights that effective interventions may need to target illness/caregiving appraisals, uncertainty, hopelessness, family support, health behaviors, self-efficacy, and coping strategies tailored to patient and caregiver needs.