Using IPF lung tissues, cultured ATII (L2) cells, and a PAI‐1 conditional knockout mouse model, we show, for the first time in this study, that PAI‐1 induces and mediates bleomycin‐ and doxorubicin‐induced ATII cell senescence in vitro and in vivo. Here, SERPINE1 is linked to idiopathic pulmonary fibrosis.