Medical staff are direct providers of medical services and a key element in the development of health services, and their life satisfaction is important to both their work satisfaction and their patients' satisfaction, subsequently influencing the quality of medical care in general. This cross-sectional study aimed to explore the mechanisms underlying the influence of perceived social support on medical staff's life satisfaction. Convenience sampling was used to recruit participants from two non-tertiary hospitals in Shaoguan City, Guandong Province, China. A total of 533 medical staff completed the Multidimensional Scale of Perceived Social Support, the Satisfaction with Life Scale, the Connor and Davidson Resilience Scale, and the depression subscale of the Depression, Anxiety, and Stress Scales (DASS-21). The results showed that perceived social support could influence medical staff's life satisfaction not only through the separate effects of resilience and depression, but also through the chain mediation effect of resilience and depression. This study suggests that reducing the depressive symptoms of medical staff and improving their perceived social support as well as resilience could help to enhance their life satisfaction.