Abstract: Objective: To explore the protective mechanism of matrine against respiratory syncytial virus (RSV) infection in mice based on the PI3K/AKT signaling pathway. Methods: The model of C57BL/6J mice infected with RSV virus by suspension nasal drops was established. The experiment was divided into three groups: control group, RSV group, RSV+matrine group, with 10 mice in each group. Pathological changes in mouse lung tissue were observed using hematoxylin-eosin staining (HE) and Masson staining. The levels of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in pulmonary alveolar lavage fluid of mice were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was performed to detect the expression of TNF-α, IL-1β, IL-6, Bax, Bcl-2, Caspase-3 and key proteins in the PI3K/AKT signaling pathway in lung tissue, and immunohistochemistry was used to detect the expression of Bax, Caspase-3, PI3K and AKT in lung tissue. Results: Compared with the control group, mice in the RSV group exhibited significant pulmonary edema, chromosomal aggregation in lung tissue cells, nuclear membrane pyknosis, marked symptoms of lung lesions, increased levels of TNF-α, IL-1β and IL-6 in lung tissue, increased expression levels of Bax and Caspase-3, and decreased expression levels of Bcl-2, P-PI3K and P-Akt (all P＜0.05). Compared with the RSV group, mice in the RSV+matrine group showed significantly alleviated pulmonary edema and pulmonary disease symptoms, significantly decreased expression levels of TNF-α, IL-1β, IL-6, Bax and Caspase-3 in lung tissue, and significantly increased expression levels of Bcl-2, P-PI3K and P-Akt (all P＜0.05). Conclusion: Matrine can inhibit the RSV-induced lung inflammation in mice and promote lung cell apoptosis, and its mechanism may be related to the activation of PI3K/AKT signaling pathway.