In this study, we investigated the immunomodulatory effects of sinensetin (SI) on RAW 264.7 macrophages and cyclophosphamide (CY)-induced immunosuppressed mice. The results showed that SI enhanced macrophage activity and promoted the secretion of NO, IL-1β, and TNF-α in vitro. Compared with the CY-induced immunosuppressed mice, in mice treated with SI, the body weights, organ indices, and total lymphocytes increased. Furthermore, SI promoted the secretion and mRNA expression of IFN-γ, IL-2, and IL-6 and reduced the damage caused by CY to the organs of the immune system. Moreover, it increased the activities of GSH-Px, CAT, SOD, and T-AOC and decreased the level of MDA. This study suggests that SI has the potential to be used as an immunity enhancer in the functional food and healthcare industries.