To investigate the intervention effects of the extracts from five traditional Chinese medicines(Glycyrrhiza uralensis, Polygonatum sibiricum, Agaricus blazei, Lonicera japonica and Sargassum) and their compound formula extract on enhancing immunity and resisting H3N2 influenza virus infection in mice with chronic fatigue syndrome(CFS), a mouse model of CFS infected with H3N2 influenza virus was established by using the method of restraint combined with sleep deprivation to induce immunocompromise and the mouse nasal drip method. The experiment mice in the drug groups were given 200 μL of the corresponding concentrated extract with a crude drug mass concentration of 300 mg/mL by gavage every day. At the end of the experiment, the organ indices, the activity of splenic lymphocytes, and pathological changes such as alveolar structure and inflammatory cell infiltration were collected. The results showed that compared with the blank control group, the spleen index of mice in the model group was extremely significantly increased to (4.43±0.14)%, while the thymus index and splenic lymphocyte proliferation activity were extremely significantly decreased, indicating a decline in the individual immunity of the mice. After infection with the H3N2 influenza virus, the mice showed pulmonary edema and hemorrhage, and the lung index was extremely significantly increased to (14.52±1.54)%, with pulmonary lesions observed. After drug administration, the compound formula extract of the five traditional Chinese medicines could promote the recovery of body mass in mice infected with the H3N2 influenza virus, significantly reduce the spleen index and increase the thymus index. The splenic lymphocyte proliferation activity was extremely significantly increased to (47.64±4.43)%, which enhanced the immune function of the mice. In addition, it reduced the lung index, exerted a good protective effect on the lung tissue structure, and alleviated and improved the viral infection symptoms of the model mice. It could be concluded that the compound formula extract of the five traditional Chinese medicines had good performance in improving the ability of mice to resist the H3N2 influenza virus by enhancing their immunity.