Meaning in life has been posited to improve psychological well-being. People facing adversities can reduce psychological distress through pursuing a sense of purpose in life. However, the effectiveness of meaning in life in promoting psychological well-being has been found varied, and what factors may affect the function of meaning in life remain unclear. In this paper, the authors suggest that resilience, the positive adaptation during or following significant adversity, can strengthen the protective effects of meaning in life on psychological well-being. To test this hypothesis, we analyzed data from a sample of 518 vulnerable children of parents living with HIV about their meaning in life, resilience, depression, and loneliness. Results showed that resilience moderated the relationship between meaning in life and depression, and between meaning in life and loneliness. Meaning in life was associated with lower levels of depression and loneliness among children high in resilience, in comparison to children low in resilience. Future interventions targeting meaning in life and well-being should consider children’s resilience, which can allow for better individualization of the treatment.