Many people living with HIV (PLWH) experience death anxiety and depression, which may impact negatively on their health-related quality of life (HRQoL). Mindfulness is a psychological resource that protects against death anxiety and depression and promotes HRQoL. Although a direct association among these variables exist, little is known about their interactive effect. This study examined the role of PLWH mindfulness in the relationship between (a) death anxiety and HRQoL, and (b) depression and HRQoL. Participants included 311 HIV patients (199 women, 122 men, mean age = 30.52) selected from a tertiary healthcare institution in Nigeria. They completed relevant measures. Results showed that mindfulness moderated the effect of death anxiety on HRQoL. Mindfulness also buffered the effect of depression on HRQoL. Clinical efforts to improve HRQoL of PLWH should consider mindfulness-based training program due to its potentials in mitigating the effects of death anxiety and depression on health and recovery.