Objective This study examined the relationship between the number of co‐existing health problems (patient comorbidities and caregiver chronic conditions) and quality of life (QOL) among patients with advanced cancer and their caregivers and assessed the mediating and moderating role of meaning‐based coping on that relationship. Methods Data came from patients with advanced cancers (breast, colorectal, lung, and prostate) and their family caregivers (N = 484 dyads). Study hypotheses were examined with structural equation modeling using the actor‐partner interdependence mediation model. Bootstrapping and model constraints were used to test indirect effects suggested by the mediation models. An interaction term was added to the standard actor‐partner interdependence model to test for moderation effects. Results More patient comorbidities were associated with lower patient QOL. More caregiver chronic conditions were associated with lower patient and caregiver QOL. Patient comorbidities and caregiver chronic conditions had a negative influence on caregiver meaning‐based coping but no significant influence on patient meaning based coping. Caregiver meaning‐based coping mediated relationships between patient comorbidities and caregiver health conditions and patient and caregiver QOL. No significant moderating effects were observed. Conclusions Despite the severity of advanced cancer for patients and caregivers, the co‐existing health problems of one member of the dyad have the potential to directly or indirectly affect the wellbeing of the other. Future research should consider how the number of patient comorbidities and caregiver chronic conditions, as well as the ability of patients and caregivers to manage those conditions, influences their meaning‐based coping and wellbeing. Copyright © 2016 John Wiley & Sons, Ltd.