Background: Authors of previous research have not yet analyzed the role of potential moderators in the relationship between depressive symptoms and quality of life (QOL). Aims: The aim of this study was to examine the moderating effect of mutuality between depressive symptoms and QOL in stroke survivor and caregiver dyads. Methods: This study used a longitudinal design with 222 stroke survivor-caregiver dyads enrolled at survivor discharge from rehabilitation hospitals. Data collection was performed for 12 months. We examined survivor and caregiver QOL dimensions (physical, psychological, social, and environmental), depression, and mutuality at baseline and every 3 months. Hierarchical linear modeling was used to test 4 longitudinal dyadic moderation models (1 for each QOL domain). Results: Survivors (50% male) and caregivers (65% female) were 70.8 (SD, 11.9) and 52.5 (SD, 13.1) years old, respectively. We observed no significant moderating effects of mutuality for survivors across the 4 dimensions of QOL over time. However, higher survivor mutuality was significantly associated with higher survivor psychological and social QOL at baseline. Regarding caregivers, caregiver mutuality significantly moderated the association between caregiver depressive symptoms and caregiver physical (B = 0.63, P < .05), psychological (B = 0.63, P < .01), and social (B = 0.95, P < .001) QOL at baseline, but not in environmental QOL. Higher caregiver mutuality was significantly associated with less improvement in caregiver physical QOL over time. Conclusions: Mutuality is a positive variable on the association between depression and QOL for both members of the dyad at discharge but may lead to declines in physical health for caregivers over time. Further work is needed to understand the role of mutuality on long-term outcomes and associations with increased care strain.