Drynariae Rhizoma (DR), a traditional Korean herbal medicine, has long been used for vital energy and to strengthen health in Korea. However, it is still unclear how DR has the effects in experimental models. We examined the immune-enhancing effect of DR in mice using the forced swimming test (FST) and in vitro tests with peritoneal macrophages. After daily oral administration of DR, blood biochemical parameters related to fatigue were measured after the FST. The immobility time in the FST was significantly decreased in the DR-treated group (100 mg/kg) on the 3th days. DR (10 and 100 mg/kg) treatment significantly decreased creatine kinase and lactic dehydrogenase levels, which are accurate indicators of muscle damage. Further, we examined how DR regulates nitric oxide (NO) production and tumor necrosis factor alpha (TNF-alpha) production and in mouse peritoneal macrophages. When DR was used in combination with recombinant interferon-gamma (rIFN-gamma), there were noticeable cooperative productions of NO and TNF-alpha. These results suggest that DR improves immune function through the changes in indicators related to fatigue and the regulatory effects on immunological parameters, such as NO and TNF-alpha productions.