Using IPF lung tissues, cultured ATII cells, and a tamoxifen‐inducible, ATII cell‐specific PAI‐1 conditional knockout mouse model generated recently in this laboratory, we show, in this study, that PAI‐1 induces p53, activates p53‐p21‐Rb cell cycle repression pathway, and mediates bleomycin‐ and doxorubicin‐induced ATII cell senescence both in vitro and in vivo. Here, SERPINE1 is linked to idiopathic pulmonary fibrosis.