Background and aim Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moor, is considered to attenuate the progression of silicosis. However, its effects and underlying mechanisms remain controversial. We aimed to identify the pharmacological mechanism of TET on silica-induced lung fibrosis and transforming growth factor (TGF)-?1 stimulated lung fibroblasts. Methods Network pharmacology was used to elucidate the biological mechanisms of TET in the treatment of pulmonary fibrosis and silicosis. TET was administered orally to a silica-induced mouse model at the early or late stage of lung fibrosis. The effects of TET on fibroblasts induced by TGF-?1 was observed in vitro. Results A total of 101 targets of TET and 7,851 pulmonary-related genes and 80 overlapping genes were analyzed. Molecular docking analysis revealed that TET binds to AKT1, PI3K, and KDR. TET treatment both at early or late phase significantly alleviated silica-induced lung fibrosis and decreased the expression of fibrotic markers in mice. TET inhibited migration, proliferation, and differentiation of TGF-?1 induced lung fibroblasts in vitro. In addition, TET ameliorated silica or TGF-?1 induced pulmonary fibrosis by inhibiting the PI3K/AKT pathway. Conclusion TET can suppress silica-induced mice pulmonary fibrosis by inhibiting the PI3K/AKT signaling pathway. (Sponsored by National Natural Science Foundation of China, 81970061)